endothelin-1 and Atherosclerosis

Phenotypic switching of vascular smooth muscle cells (VSMCs) plays a key role in atherosclerosis. Hyperhomocysteinemia (HHcy) is an independent risk factor for atherosclerosis. HHcy induces phenotypic switching of VSMCs, but the mechanism is unclear. Endothelin-1 (ET-1) promotes proliferation and migration of VSMCs by inducing phenotypic switching during atherosclerosis. This review examined recent findings on the relationship between HHcy or the ET-1 system (including ET-1 and its receptors) and phenotypic switching of VSMCs as well as the molecular mechanism of HHcy-regulated ET-1 signaling. In particular, we focused on the potential mechanisms and pharmacological targets of phenotypic switching of VSMCs regulated by HHcy through ET-1 signaling.

Topics: Animals; Atherosclerosis; Cell Proliferation; Endothelin-1; Humans; Hyperhomocysteinemia; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phenotype; Phosphorylation; Signal Transduction

Healthy vascular endothelial cells regulate vascular tone and permeability, prevent vessel wall inflammation, enhance thromboresistance, and contribute to general vascular health. Furthermore, they perform important functions including the production of vasoactive substances such as nitric oxide (NO) and endothelium-derived hyperpolarizing factors, as well as the regulation of smooth muscle cell functions. Conversely, vascular endothelial dysfunction leads to atherosclerosis, thereby enhancing the risk of stroke, myocardial infarction, and other cardiovascular diseases (CVDs). Observational studies and randomized trials showed that green tea intake was inversely related to CVD risk. Furthermore, evidence indicates that epigallocatechin gallate (EGCG) found in green tea might exert a preventive effect against CVDs. EGCG acts as an antioxidant, inducing NO release and reducing endothelin-1 production in endothelial cells. EGCG enhances the bioavailability of normal NO by reducing levels of the endogenous NO inhibitor asymmetric dimethylarginine. Furthermore, it inhibits the enhanced expression of adhesion molecules such as vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 and attenuates monocyte adhesion. In addition, EGCG prevents enhanced oxidative stress through the Nrf2/HO-1 pathway. These effects indicate that it might prevent the production of reactive oxygen species, inhibit inflammation, and reduce endothelial cell apoptosis during the initial stages of atherosclerosis. The current review summarizes recent research in this area and discusses novel findings regarding the protective effect of EGCG on endothelial dysfunction and CVDs in general.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Atherosclerosis; Catechin; Cell Adhesion Molecules; Endothelial Cells; Endothelin-1; Endothelium, Vascular; Humans; Nitric Oxide; Oxidative Stress

Age-associated structural and functional remodeling of the arterial wall produces a productive environment for the initiation and progression of hypertension and atherosclerosis. Chronic aging stress induces low-grade proinflammatory signaling and causes cellular proinflammation in arterial walls, which triggers the structural phenotypic shifts characterized by endothelial dysfunction, diffuse intimal-medial thickening, and arterial stiffening. Microscopically, aged arteries exhibit an increase in arterial cell senescence, proliferation, invasion, matrix deposition, elastin fragmentation, calcification, and amyloidosis. These characteristic cellular and matrix alterations not only develop with aging but can also be induced in young animals under experimental proinflammatory stimulation. Interestingly, these changes can also be attenuated in old animals by reducing low-grade inflammatory signaling. Thus, mitigating age-associated proinflammation and arterial phenotype shifts is a potential approach to retard arterial aging and prevent the epidemic of hypertension and atherosclerosis in the elderly.

Topics: Aging; Animals; Arteries; Atherosclerosis; Endothelial Cells; Endothelin-1; Endothelium, Vascular; Humans; Hypertension; Inflammation; Phenotype; Renin-Angiotensin System; Sympathetic Nervous System; Syndrome; Vascular Stiffness

Adipose tissue is recognized as a rich source of proinflammatory mediators that may directly contribute to vascular injury, insulin resistance, and atherogenesis. Many studies have shown that adiponectin has antiatherogenic and anti-inflammatory properties. Adiponectin acts not only as a factor increasing insulin sensitivity, and the protective effect may result from its ability to suppress production of proinflammatory cytokines. It negatively regulates the expression of TNF-alpha and C-reactive protein (CRP) in adipose tissue; reduces expression of vascular and intracellular adhesion molecules (VCAM-1, ICAM-1), E-selectin, interleukin-8 (IL-8). Hyperleptinemia has been linked with the development of hypertension and endothelial dysfunction/atherosclerosis, two main pathophysiological conditions associated with cardiovascular disease development. Leptin-mediated increases in sympathetic nervous system activity may be among the principal mechanisms evoking obesity related hypertension. Leptin stimulates the secretion of proinflammatory cytokines, and increases the release of endothelin-1 (ET-1), which may promote hypertension. Increased serum levels of asymmetric dimethylarginine (ADMA), a physiological regulator of the biosynthesis of nitric oxide (NO), promote the process of atherosclerosis, leading to the occurrence of endothelial dysfunction and cardiovascular disease.

Topics: Adiponectin; Arginine; Atherosclerosis; C-Reactive Protein; E-Selectin; Endothelin-1; Humans; Intercellular Adhesion Molecule-1; Interleukin-8; Leptin; Nitric Oxide; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

The aim of this review article is to summarize the current knowledge about mechanisms that connect blood pressure regulation and hypercholesterolemia, the mutual interaction between hypertension and hypercholesterolemia, and their influence on atherosclerosis development. Our research shows that at least one-third of the population of Western Europe has hypertension and hypercholesterolemia. Several biohumoral mechanisms could explain the relationship between hypertension and hypercholesterolemia and the association between these risk factors and accelerated atherosclerosis. The most investigated mechanisms are the renin-angiotensin-aldosterone system, oxidative stress, endothelial dysfunction, and increased production of endothelin-1. Arterial hypertension is frequently observed in combination with hypercholesterolemia, and this is related to accelerated atherosclerosis. Understanding the mechanisms behind this relationship could help explain the benefits of therapy that simultaneously reduce blood pressure and cholesterol levels.

Topics: Antihypertensive Agents; Atherosclerosis; Blood Pressure; Endothelin-1; Endothelium, Vascular; Humans; Hypercholesterolemia; Hypertension; Hypolipidemic Agents; Inflammation Mediators; Lipids; Muscle, Smooth, Vascular; Oxidative Stress; Renin-Angiotensin System; Risk Factors

Arterial aging is the major contributing factor to increases in the incidence and prevalence of cardiovascular disease, due mainly to the presence of chronic, low-grade, 'sterile' arterial inflammation. Inflammatory signaling driven by the angiotensin II cascade perpetrates adverse age-associated arterial structural and functional remodeling. The aged artery is characterized by endothelial disruption, enhanced vascular smooth muscle cell (VMSC) migration and proliferation, extracellular matrix (ECM) deposition, elastin fracture, and matrix calcification/amyloidosis/glycation. Importantly, the molecular mechanisms of arterial aging are also relevant to the pathogenesis of hypertension and atherosclerosis. Age-associated arterial proinflammation is to some extent mutable, and interventions to suppress or delay it may have the potential to ameliorate or retard age-associated arterial diseases.

Topics: Aged; Aging; Angiotensin II; Animals; Antigens, Surface; Arteries; Arteritis; Atherosclerosis; Calpain; Chemokine CCL2; Endothelin-1; Humans; Hypertension; Inflammation; Inflammation Mediators; Matrix Metalloproteinase 2; Middle Aged; Milk Proteins; Muscle, Smooth, Vascular; Nitric Oxide; Reactive Oxygen Species; Receptors, CCR2; Transforming Growth Factor beta1

The discovery of endothelin (ET) in 1988 has led to considerable effort to unravel its implication in health and disease and the mechanisms evoked by ET. ET-1 and related signaling aberrancies are believed to be implicated in the pathogenesis of diverse cardiovascular diseases, such as hypertension, atherosclerosis, hypertrophy and diabetes. The endothelin system consists of three potent vasoconstrictive isopeptides, ET-1, ET-2 and ET-3, signaling through two G protein coupled receptors, ETA and ETB, which are linked to multiple signaling pathways. Activated signaling transduction pathways include the modulation of the adenylyl cyclase/cAMP pathway through stimulatory (Gs) and inhibitory (Gi) G proteins, activation of the phosphoinositide pathway through the activation of proteins Gq/11, generation of oxidative stress, growth factor receptor-related mitogenic events, such as the activation of phosphatidylinositol-3 kinase pathway, phosphoinositide pathway and activation of the mitogen-activated protein (MAP) kinase cascade. The levels of ETA and ETB receptors as well as the signaling pathways activated by these receptors are altered in several cardiovascular diseases including hypertension, hypertrophy, atherosclerosis, diabetes, etc. In this review, we provide an overview of the signaling events modulated by ET-1 in vascular smooth muscle cells in both physiological and pathological conditions.

Topics: Adenylyl Cyclases; Animals; Atherosclerosis; Calcium; Diabetes Mellitus; Endothelin-1; Humans; Hypertension; MAP Kinase Signaling System; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Oxidative Stress; Receptor, Endothelin A; Receptor, Endothelin B; Signal Transduction

The process of vascular aging encompasses alterations in the function of endothelial (ECs) and vascular smooth muscle cells (VSMCs) via oxidation, inflammation, cell senescence and epigenetic modifications, increasing the probability of atherosclerosis. Aged vessels exhibit decreased endothelial antithrombogenic properties, increased reactive oxygen species generation, inflammatory signaling and migration of VSMCs to the subintimal space, impaired angiogenesis and increased elastin degradation. The key initiating step in atherogenesis is subendothelial accumulation of apolipoprotein B-containing low-density lipoproteins resulting in activation of ECs and recruitment of monocytes. Activated ECs secrete 'chemokines' that interact with cognate chemokine receptors on monocytes and promote directional migration. Recruitment of immune cells establishes a proinflammatory status, further causing elevated oxidative stress, which in turn triggers a series of events including apoptotic or necrotic death of vascular and nonvascular cells. Increased oxidative stress is also considered to be a key factor in mechanisms of aging-associated changes in tissue integrity and function. Experimental evidence indicates that insulin-like growth factor-1 exerts antioxidant, anti-inflammatory and pro-survival effects on the vasculature, reducing atherosclerotic plaque burden and promoting features of atherosclerotic plaque stability.

Topics: Adaptor Proteins, Signal Transducing; Aging; Animals; Anti-Inflammatory Agents; Apolipoproteins E; Atherosclerosis; Cell Movement; Cellular Senescence; Endothelial Cells; Endothelin-1; Humans; Hypertension; Insulin-Like Growth Factor I; Lipoproteins, LDL; Mice; Monocytes; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Oxidative Stress; Plaque, Atherosclerotic; Receptor, IGF Type 1; Regeneration

Since its identification in 1988 and the recognition of its primary role as a potent vasoconstrictor, endothelin has been extensively studied and is now considered as a ubiquitous protein, involved in important aspects of human homeostasis as well as in several pathophysiological pathways, mostly associated with cardiovascular disease. From an evolutionary point of view, endothelin consists a primitive molecule with the rare characteristic of being exactly the same in all mammals, thus permitting scientists to perform experiments in animals and doing predictions for humans. The understanding of its contribution to the genesis, evolution and maintenance of disease through activation of special receptor subtypes has led to the development of both selective and unselective receptor antagonists. Despite the disappointing results of these antagonists in the field of heart failure, almost from the initial animal trials of bosentan, a dual endothelin receptor antagonist, in pulmonary arterial hypertension, it has been demonstrated that the drug leads at least to hemodynamic and clinical improvement of the patients, thus receiving official approval for the management of this rare but eventually lethal disease. Resistant hypertension is another area where endothelin receptor blockers might potentially play a role, while the pathophysiological role of endothelin in atherosclerotic coronary artery disease is well-established and the relative research goes on. The main goal of this review is to describe the endothelin system and mostly to enlighten its role in pathophysiologic pathways, as well to state the relative research in the various fields of cardiovascular disease and also highlight its prognostic significance wherever there exists one.

Topics: Animals; Atherosclerosis; Atrial Fibrillation; Bosentan; Cardiovascular Diseases; Coronary Artery Disease; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Humans; Hypertension, Pulmonary; Phenylpropionates; Predictive Value of Tests; Pyridazines; Receptors, Endothelin; Sulfonamides

The purpose of this review of the vascular biology of endothelin-1 (ET-1) is the presentation of recent data including the use of endothelin-receptor antagonists for the treatment of hypertension.. Recent discoveries regarding the pharmacology of ET-1 in the vascular wall and its effect on signalling transduction and gene expression in vascular smooth muscle cells are reviewed, as well as mechanisms controlling blood pressure in normal conditions and in hypertension, discovered using genetically modified models. Finally, studies of endothelin antagonists for treatment of hypertension will be summarized.. Pharmacological studies demonstrate that calcitonin gene-related peptide is a physiological antagonist of ET-1 that terminates the long-lasting contraction induced by ET-1. ET-1-induced rise in [Ca]i involves the newly described stromal-interaction molecule-1/orai1 pathway to increase store-operated calcium entry. Sensitization of contractile proteins to calcium during ET-1-induced contraction of vascular smooth muscle cells includes activation of p63Rho guanine nucleotide exchange factor and increase in O-GlcNAcylation, a form of posttranslational modification. Genetically modified mice have demonstrated that endothelial ET-1 is involved in the regulation of normal blood pressure and development of vascular disease. Gene expression induced by endothelial overexpression of ET-1 in mice demonstrated upregulation of lipid metabolism, inflammatory and signal transduction genes. Crossing these mice with apoE mice was associated with acceleration of atherosclerosis on a high-fat diet and blood pressure elevation. Finally, the DORADO clinical trial has demonstrated that the ETA-receptor antagonist darusentan is able to decrease the blood pressure of patients with refractory hypertension.

Topics: Animals; Atherosclerosis; Blood Pressure; Endothelin Receptor Antagonists; Endothelin-1; Gene Expression Regulation; Humans; Hypertension; Muscle, Smooth, Vascular; Signal Transduction

Increased numbers of mast cells have been reported in explanted human hearts with dilated cardiomyopathy and in animal models of experimentally induced hypertension, myocardial infarction, and chronic volume overload secondary to aortocaval fistula and mitral regurgitation. Accordingly, mast cells have been implicated to have a major role in the pathophysiology of these cardiovascular disorders. In vitro studies have verified that mast cell proteases are capable of activating collagenase, gelatinases and stromelysin. Recent results have shown that with chronic ventricular volume overload, there is an elevation in mast cell density, which is associated with a concomitant increase in matrix metalloproteinase (MMP) activity and extracellular matrix degradation. However, the role of the cardiac mast cell is not one dimensional, with evidence from hypertension and cardiac transplantation studies suggesting that they can also assume a pro-fibrotic phenotype in the heart. These adverse events do not occur in mast cell deficient rodents or when cardiac mast cells are pharmacologically prevented from degranulating. This review is focused on the regulation and dual roles of cardiac mast cells in: (i) activating MMPs and causing myocardial fibrillar collagen degradation and (ii) causing fibrosis in the stressed, injured or diseased heart. Moreover, there is strong evidence that premenopausal female cardioprotection may at least partly be due to gender differences in cardiac mast cells. This too will be addressed.

Topics: Animals; Atherosclerosis; Cardiovascular Diseases; Cell Differentiation; Cell Proliferation; Complement C5a; Endothelin-1; Female; Heart Failure; Heart Transplantation; Hematopoietic Stem Cells; Humans; Hypertension; In Vitro Techniques; Male; Mast Cells; Myocardial Infarction; Myocardial Reperfusion Injury; Myocarditis; Neuropeptides; Reactive Oxygen Species; Sex Characteristics; Ventricular Remodeling

Benign prostatic hyperplasia (BPH) is a common disease in older men that can lead to lower urinary tract symptoms (LUTS). Male sexual dysfunction is also an age-related condition. Epidemiological studies have confirmed an association between BPH/LUTS and sexual dysfunction in ageing men that is independent of the effects of age, other co-morbidities and lifestyle factors. Proposed pathophysiological mechanisms for BPH/LUTS-associated sexual dysfunction include the nitric oxide/cyclic guanosine monophosphate (NO/cGMP) pathway, rho-kinase and endothelin-1 activity, autonomic nervous system overactivity and the metabolic syndrome, and pelvic organ atherosclerosis. Both BPH/LUTS and sexual dysfunction can have a substantial negative impact on a man's quality of life. However, urologists and primary care physicians appear to under-recognise sexual dysfunction in men with BPH/LUTS. Current guidelines recommend alpha-blockers and 5-alpha reductase inhibitors, either alone or in combination, among appropriate medical treatment options for BPH/LUTS. Randomised, controlled trials demonstrate that these therapies can be associated with sexual adverse effects (AEs) such as loss of libido, erectile dysfunction and ejaculatory disorders. Sexual dysfunction should be fully evaluated in men requiring treatment for BPH/LUTS using validated questionnaires. Management of sexual dysfunction in men treated for BPH/LUTS should involve assessment of co-morbidities and concomitant medications, consideration of lifestyle interventions such as weight loss and increased physical activity to improve risk factors and, if necessary, introduction of pharmacotherapies. In addition, physicians should provide patients with proper counselling on the possible sexual AEs of medical therapies for BPH/LUTS and their impact on sexual satisfaction, while being aware of the possibility that counselling in itself is likely to influence reported rates of sexual dysfunction.

Topics: 5-alpha Reductase Inhibitors; Adrenergic alpha-Antagonists; Adult; Aged; Atherosclerosis; Autonomic Nervous System Diseases; Cyclic GMP; Drug Combinations; Endothelin-1; Humans; Male; Metabolic Syndrome; Middle Aged; Nitric Oxide; Prostatic Hyperplasia; Prostatism; rho-Associated Kinases; Sexual Dysfunction, Physiological

One year after the revelation by Dr. Furchgott in 1980 that the endothelium was obligatory for acetylcholine to relax isolated arteries, it was clearly shown that the endothelium could also promote contraction. In 1988, Dr. Yanagisawa's group identified endothelin-1 (ET-1) as the first endothelium-derived contracting factor. The circulating levels of this short (21-amino acid) peptide were quickly determined in humans, and it was reported that, in most cardiovascular diseases, circulating levels of ET-1 were increased, and ET-1 was then tagged as "a bad guy." The discovery of two receptor subtypes in 1990, ET(A) and ET(B), permitted optimization of the first dual ET-1 receptor antagonist in 1993 by Dr. Clozel's team, who entered clinical development with bosentan, which was offered to patients with pulmonary arterial hypertension in 2001. The revelation of Dr. Furchgott opened a Pandora's box with ET-1 as one of the actors. In this brief review, we will discuss the physiological and pathophysiological role of endothelium-derived ET-1 focusing on the regulation of the vascular tone, and as much as possible in humans. The coronary bed will be used as a running example in this review because it is the most susceptible to endothelial dysfunction, but references to the cerebral and renal circulation will also be made. Many of the cardiovascular complications associated with aging and cardiovascular risk factors are initially attributable, at least in part, to endothelial dysfunction, particularly dysregulation of the vascular function associated with an imbalance in the close interdependence of nitric oxide and ET-1.

Topics: Aging; Animals; Atherosclerosis; Coronary Vasospasm; Coronary Vessels; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Humans; Peptides, Cyclic; Receptor, Endothelin A; Receptor, Endothelin B; Vasoconstriction; Vasodilation

Topics: Atherosclerosis; Brachial Artery; Cardiovascular Diseases; Diabetic Angiopathies; Endothelin-1; Endothelium, Vascular; Humans; Ischemic Attack, Transient; Meta-Analysis as Topic; Nitric Oxide; Risk Factors; Tunica Intima; Tunica Media

Due to its dependence on intracellular development Chlamydia pneumoniae has developed numerous strategies to create an adequate environment within its host cells ensuring both chlamydial reproduction and target cell survival. The bacterium that has been related to atherogenesis due to its presence in vascular tissue is able to enter a persistent state of chronic infection in the vasculature that escapes antibiotic targeting. Ingestion of the bacterium results in severe modifications and reprogramming of signalling pathways and the metabolism of the host cell. Processes range from the prevention of direct lysosomal destruction of chlamydial inclusions to the inhibition of host cell apoptosis and an enhanced cellular glucose uptake to maintain energy-consuming mechanisms. Furthermore, infection regularly causes the development of a proinflammatory and proproliferative phenotype in the host cell in vitro, ex vivo and in vivo and own new findings suggest a detrimental proliferative loop within vascular cells upon a modified endothelin-1 axis demonstrating a potential for proatherosclerotic processes in early and progressed atherosclerosis. This review displays crucial mechanisms of Chlamydia pneumoniae-induced interactions with vascular host cell signalling cascades with an emphasis on mitogenic and inflammatory processes as well as target cell activation.

Topics: Atherosclerosis; Blood Vessels; Chlamydia Infections; Chlamydophila pneumoniae; Endothelin-1; Host-Pathogen Interactions; Humans; MAP Kinase Signaling System; Models, Biological; Neovascularization, Pathologic; Nod Signaling Adaptor Proteins; Signal Transduction; Toll-Like Receptors

The formation and progression of atherosclerotic plaques followed by rupture, thrombus formation and vessel blockage leads to ischemic tissue damage and the clinical condition underlying most cardiovascular disease. Therapeutic agents for the prevention of atherosclerosis have all targeted epidemiologically-identified and relatively easily measured risk factors (e.g. lipids and blood pressure). This strategy has proven somewhat effective but is of less than optimal efficacy as rates of cardiovascular disease remain high. Treatment targeting the mechanisms of atherosclerosis in the vessel wall is a conceptually attractive proposition to complement the risk factor directed strategy. Vascular smooth muscle cells (VSMC) are the major cellular component of the vascular media and migration and proliferation leads to the formation of the neointima the development of which renders the vessels particularly sensitive to atherosclerosis. Numerous hormones and growth factors act on VSMC to cause migration, proliferation and the secretion of extracellular matrix and modulation or dysfunction of these processes is the most likely cause of atherosclerosis. Endothelin-1 (ET-1) is a 21 amino acid peptide that acts on 7 transmembrane G protein coupled receptors to elicit a plethora of responses that can modulate the behaviour of VSMCs and thus impact on the development of atherosclerosis. ET-1 is elevated in atherosclerotic plaques. People with diabetes have accelerated atherosclerosis and also show elevated plasma levels of ET-1. This review addresses the actions of ET-1 on VSMC and the signalling pathways through which it mediates its effects as the latter represent potential therapeutic targets for the prevention of atherosclerosis.

Topics: Animals; Atherosclerosis; Clinical Trials as Topic; Endothelin Receptor Antagonists; Endothelin-1; Humans; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Receptors, Endothelin

Vascular inflammation underlies the pathogenesis of atherosclerosis. Atherosclerotic changes in the vasculature lead to conditions such as coronary artery disease and stroke, which are the major causes of morbidity and mortality worldwide. Epidemiological studies in premenopausal women suggest a beneficial role for estrogen in preventing vascular inflammation and consequent atherosclerosis. However, the benefits of estrogen areabsent or even reversed in older postmenopausal subjects. The modulation of inflammation by estrogen under different conditions might explain this discrepancy. Estrogen exerts its antiinflammatory effects on the vasculature through different mechanisms such as direct antioxidant effect, generation of nitric oxide, prevention of apoptosis in vascular cells and suppression of cytokines and the renin-angiotensin system. On the other hand, estrogen also elicits proinflammatory changes under certain conditions, which are less completely understood. Some of the mechanisms underlying a possible proinflammatory role for estrogen include increased expression of the proinflammatory receptor for advanced glycation end products, increased tyrosine nitration of cellular proteins, and generation of reactive oxygen species through an uncoupled eNOS. In this review, we have presented evidence for both antiinflammatory and proinflammatory pathways modulated by estrogen and how interactions among such pathways might determine the effects of estrogen on the vascular system.

Topics: Aging; Animals; Antioxidants; Apoptosis; Atherosclerosis; Cytokines; Endothelin-1; Estrogens; Female; Humans; Inflammation; Models, Biological; Nitric Oxide; Permeability; Tumor Necrosis Factor-alpha

Atherosclerosis is the primary ischaemic vascular condition underlying a majority of cardiovascular disease related deaths. Endothelin-1 is a vasoactive peptide agent upregulated in atherosclerosis and in conjunction with its G protein-coupled receptors exerts diverse actions on all cells of the vasculature in particular vascular smooth muscle cells (VSMC). The effects of endothelin-1 include cell proliferation, migration and contraction, and the induction of extracellular matrix components and growth factors. VSMC as the major component of the neointima in atherosclerotic plaques accordingly play a key role in atherogenesis. In this review we examine classic and novel signalling pathways activated by endothelin-1 in VSMC (including phospholipase C, adenylate cyclase, Rho kinase, transactivation of receptor tyrosine kinases, mitogen activated protein kinase cascades and beta-arrestin) and their likely impact on the development and progression of atherosclerosis.

Topics: Animals; Atherosclerosis; Endothelin-1; Extracellular Matrix; Gene Expression Regulation; Humans; MAP Kinase Signaling System; Models, Biological; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Peptides; Signal Transduction; Transcriptional Activation

Endothelial cells synthesize and release various factors that regulate angiogenesis, inflammatory responses, hemostasis, as well as vascular tone and permeability. Endothelial dysfunction has been associated with a number of pathophysiological processes. Oxidative stress appears to be a common denominator underlying endothelial dysfunction in cardiovascular diseases. However, depending on the pathology, the vascular bed studied, the stimulant, and additional factors such as age, sex, salt intake, cholesterolemia, glycemia, and hyperhomocysteinemia, the mechanisms underlying the endothelial dysfunction can be markedly different. A reduced bioavailability of nitric oxide (NO), an alteration in the production of prostanoids, including prostacyclin, thromboxane A2, and/or isoprostanes, an impairment of endothelium-dependent hyperpolarization, as well as an increased release of endothelin-1, can individually or in association contribute to endothelial dysfunction. Therapeutic interventions do not necessarily restore a proper endothelial function and, when they do, may improve only part of these variables.

Topics: Animals; Atherosclerosis; Cardiovascular Diseases; Endothelin-1; Endothelium, Vascular; Hemostasis; Humans; Hypertension; Inflammation; Nitric Oxide; Oxidative Stress; Rats; Rats, Inbred SHR; Reactive Oxygen Species

The vascular endothelium synthesizes and releases a spectrum of vasoactive substances and therefore plays a fundamental role in the basal and dynamic regulation of the circulation. Nitric oxide (NO)-originally described as endothelium-derived relaxing factor-is released from endothelial cells in response to shear stress produced by blood flow, and in response to activation of a variety of receptors. After diffusion from endothelial to vascular smooth muscle cells, NO increases intracellular cyclic guanosine-monophosphate concentrations by activation of the enzyme guanylate cyclase leading to relaxation of the smooth muscle cells. NO has also antithrombogenic, antiproliferative, leukocyte-adhesion inhibiting effects, and influences myocardial contractility. Endothelium-derived NO-mediated vascular relaxation is impaired in spontaneously hypertensive animals. NO decomposition by free oxygen radicals is a major mechanism of impaired NO bioavailability. The resulting imbalance of endothelium-derived relaxing and contracting substances disturbs the normal function of the vascular endothelium. Endothelin acts as the natural counterpart to endothelium-derived NO. Besides its arterial blood pressure rising effect in humans, endothelin-1 induces vascular and myocardial hypertrophy, which are independent risk factors for cardiovascular morbidity and mortality. Current therapeutic strategies concentrate mainly on lowering low-density lipoprotein cholesterol and an impressive reduction in the risk for cardiovascular morbidity and mortality has been achieved. Inflammatory mechanisms play an important role in vascular disease and inflammatory plasma markers correlate with prognosis. The production of reactive oxygen species under pathological conditions may represent an important inflammatory trigger. Novel therapeutic strategies specifically targeting inflammation thus bear great potential for the prevention and treatment of atherosclerotic vascular disease. In this context, the vascular actions of flavanol-rich cocoa, particularly with regard to enhanced NO synthesis and endothelial function observed in humans following consumption, warrants further attention. This review discusses pharmacological and dietary intervention.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Arginine; Atherosclerosis; Biopterins; Cacao; Calcium Channel Blockers; Cyclooxygenase Inhibitors; Dyslipidemias; Endothelin-1; Endothelins; Endothelium, Vascular; Flavonoids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Lipoproteins, HDL; Nitric Oxide; Oxidative Stress; Reactive Oxygen Species

This review summarises the role of the endothelium in the regulation of the vascular tone, emphasizes the importance of nitric oxide and endothelin at the vasodilator and vasoconstrictor physiological processes. Mainly, the nitric oxide is responsible for the basal tone of the vasculature, but plenty of modifying factors (endothelin, angiotensin-II, prostacyclin) have also important effects. Endothelial dysfunction observable in hypertension, which characterised by disorder of the endothelium-dependent relaxation, and predominance of the vasoconstrictor processes. Disorder of synthesis, decreased biological activity and increased degradation of the nitric oxide could play a role in the fall of the basal vasodilator tone, as well as other factors influencing the production of nitric oxide. Due to a relaxation disorder, the vasoconstrictor endothelin come to the front, following morphological changes of the vessels, afterwards. Endothelial dysfunction of the medium size arteries lead to thickening of the intima, what can follow by non-invasive measurements at the common carotid arteries. It is unambiguous in hypertensive patients that augmenting the tone of the resistance vessels, the peripheral vascular tone increases. It is proved in hypertensive adults that damaged function of the cerebral arterioles results in decrease of the vasoreactivity following a hypo- or hypercapnic stimuli. The imbalance of the nitric oxide-endothelin system is not only a process what helps to partly explain the pathophysiology of hypertension, but also a therapeutic aim preventing the process of atherosclerosis.

Topics: Atherosclerosis; Endothelin-1; Endothelium, Vascular; Humans; Hypertension; Nitric Oxide; Vasoconstriction

Endothelial dysfunction is a characteristic aspect of most of the conditions associated with atherosclerosis and is commonly found as an early feature in atherothrombotic vascular disease. An appreciation of the underlying mechanisms of endothelial function, as well as dysfunction, is essential as this has critical influence on the different methods in the assessment of endothelial function and effects of various treatments on its quantification. Furthermore, endothelial dysfunction is recognised as a type of 'target organ damage' in common cardiovascular conditions (e.g., hypertension) and the area is of increasing interest for new drug development, as therapies that modulate the endothelium will have added advantages; thus, for the development of new/experimental drugs, an awareness of ways to assess the endothelium is necessary. In this review, an overview of different methods including biochemical markers, and invasive and non-invasive tools, to determine endothelial function is presented as well as their clinical relevance. Furthermore, the effects of various treatments on endothelial dysfunction and their underlying mechanisms are elucidated.

Topics: Animals; Arginine; Atherosclerosis; C-Reactive Protein; Endothelial Cells; Endothelin-1; Endothelium, Vascular; Humans; Nitric Oxide; Stem Cells; Tissue Plasminogen Activator; Vascular Cell Adhesion Molecule-1; Vasodilation; von Willebrand Factor

Topics: Adult; Animals; Apoptosis; Arginine; Atherosclerosis; Cardiovascular Diseases; Cells, Cultured; Child; Endothelial Cells; Endothelin-1; Endothelium, Vascular; Epoprostenol; Female; GTP-Binding Proteins; Hemodynamics; Humans; Macrophages; Male; Multienzyme Complexes; Mutation; NADH, NADPH Oxidoreductases; NADPH Oxidases; Nitric Oxide; Nitric Oxide Synthase; Oxidative Stress; Pregnancy; Rats; Rats, Inbred Dahl; Reactive Oxygen Species; Risk Factors; RNA, Messenger

The vascular endothelium synthesizes and releases a spectrum of vasoactive substances and therefore plays a fundamental role in the basal and dynamic regulation of the circulation. Nitric oxide (NO)--originally described as endothelium-derived relaxing factor--is released from endothelial cells in response to shear stress produced by blood flow, and in response to activation of a variety of receptors. After diffusion from endothelial to vascular smooth muscle cells, NO increases intracellular cyclic guanosine-monophosphat concentrations by activation of the enzyme guanylate cyclase leading to relaxation of the smooth muscle cells. NO has also antithrombogenic, antiproliferative, leukocyte-adhesion inhibiting effects, and influences myocardial contractility. Endothelium-derived NO-mediated vascular relaxation is impaired in spontaneously hypertensive animals. NO decomposition by free oxygen radicals is a major mechanism of impaired NO bioavailability. The resulting imbalance of endothelium-derived relaxing and contracting substances disturbs the nor- mal function of the vascular endothelium. Endothelin acts as the natural counterpart to endothelium-derived NO. In man, besides its effect of increasing arterial blood pressure, ET-1 induces vascular and myocardial hypertrophy, which are independent risk factors for cardiovascular morbidity and mortality. Current therapeutic strategies concentrate mainly on lowering of low-density lipoprotein cholesterol and an impressive reduction in the risk for cardiovascular morbidity and mortality has been achieved. Inflammatory mechanisms play an important role in vascular disease and inflammatory plasma markers correlate with prognosis. Novel therapeutic strategies specifically targeting inflammation thus bear great potential for the prevention and treatment of atherosclerotic vascular disease.

Topics: Adrenergic beta-Antagonists; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Atherosclerosis; Calcium Channel Blockers; Cholesterol; Cyclooxygenase Inhibitors; Endothelin-1; Endothelium, Vascular; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipoproteins, HDL; Vitamin E

The role of chronic inflammation in the pathogenesis of the acute coronary syndromes has received increasing attention since active plaques rich in macrophages (Mphi's) are more prone to rupture whereas plaques rich in myofibroblasts are considered to be stable. Functionally, active plaques show a locally enhanced vasoreactivity. Endothelin-1 (ET-1) a potent vasoconstrictor acts in a paracrine fashion to regulate vascular tone. ET-1 is also produced by inflammatory cells suggesting a role for ET-1 in inflammation. Additionally, ET-1 is a mitogen. Endothelin converting enzyme-1 (ECE-1) activates ET-1 and may thus contribute to the regulation of vascular tone and cell growth during atherosclerosis. We evaluated the presence of ECE-1 and big ET-1/ET-1 and the activity of ECE-1 in different plaque types. Together with ET-1, ECE-1 is present in endothelial cells (ECs), vascular smooth muscle cells (VSMCs) and Mphi's. ECE-1 activity and ET-1-immunoreactivity (IR) both are upregulated during the progression of atherosclerosis from a non-inflammatory to an inflammatory stage. Thus, enhanced production of active ET-1 may contribute to cell growth and regulation of vascular tone in advanced plaques and also in very early stages of atherosclerosis. Furthermore, we examined the presence of ET-1 in coronary plaque tissue obtained by directional coronary atherectomy. ET-1 IR localized to plaque components indicative of chronic inflammation. Semiquantitative analysis of ET-1 IR revealed significantly higher staining grades in active coronary lesions compared with nonactive lesions. The increased ET-1 content in active coronary lesions may be beneficial to the stabilization of the vessel wall after plaque rupture and disadvantageous because it may lead to vasospasm and to the progression of atherosclerosis.

Topics: Aspartic Acid Endopeptidases; Atherosclerosis; Coronary Vessels; Endothelin A Receptor Antagonists; Endothelin-1; Endothelin-Converting Enzymes; Humans; Immunohistochemistry; Mammary Arteries; Metalloendopeptidases; Microscopy, Immunoelectron; Tunica Intima

Experimental and clinical studies have demonstrated the effect of phytosterols (PS) on reducing plasma levels of cholesterol and LDL-c, but the effects of plant sterols beyond cholesterol-lowering are still questionable. Since inflammation and endothelial dysfunction are involved in the pathogenesis of atherosclerosis, this study aims to evaluate the effect of PS on biomarkers involved in atherosclerosis progression and whether these effects are independent of alterations in plasma LDL-c levels. Thirty-eight moderately hypercholesterolemic volunteers (58 ± 12 years; LDL-c ≥ 130 mg/dL) were randomly assigned to consume 400 mL/day of soy milk or soy milk + PS (1.6 g/day) for 4 weeks in a double-blind, placebo-controlled, cross-over study. Blood samples were collected and lipid profiles and biomarkers for inflammation and endothelial dysfunction determined. The results showed that PS treatment reduced endothelin-1 plasma concentration by 11% (

Topics: Adult; Aged; Apolipoproteins B; Atherosclerosis; Biomarkers; Brazil; C-Reactive Protein; Cholesterol; Cholesterol, LDL; Cross-Over Studies; Dietary Supplements; Double-Blind Method; Endothelin-1; Female; Humans; Hypercholesterolemia; Inflammation; Lipids; Male; Middle Aged; Phytosterols; Plasma; Soy Milk; Sterols; Triglycerides

Previous studies of the health effects of low-fat milk or dairy consumption on the metabolic syndrome have yielded inconsistent results. The present study aimed to investigate the effects of low-fat milk consumption on traits associated with the metabolic syndrome, as well as inflammatory and atherogenic biomarkers, in Korean adults with the metabolic syndrome.. Overweight Koreans with the metabolic syndrome (n = 58) were recruited and randomly assigned to either the low-fat milk or control group. The low-fat milk group was instructed to consume two packs of low-fat milk per day (200 mL twice daily) for 6 weeks, and the control group was instructed to maintain their habitual diet. Clinical investigations were conducted during the screening visit, on study day 0, and after 6 weeks.. No significant differences in changes in body mass index, blood pressure, lipid profile and adiponectin levels, as well as levels of inflammatory markers, oxidative stress markers and atherogenic markers, were found between the low-fat milk and control groups. However, compared to the controls, significant favourable decreases in serum soluble vascular adhesion molecule-1 and endothelin-1 levels were found in the 12 subjects with high blood pressure and in the 18 subjects with hypertriglyceridaemia in the low-fat milk group.. The present study did not demonstrate an overall beneficial effect of low-fat milk consumption in subjects with the metabolic syndrome. However, low-fat milk consumption may have a favourable effect on atherogenic markers in subjects with high blood pressure or hypertriglyceridaemia.

Topics: Adult; Animals; Atherosclerosis; Biomarkers; Body Mass Index; Diet, Fat-Restricted; Endothelin-1; Follow-Up Studies; Humans; Hypertension; Hypertriglyceridemia; Inflammation Mediators; Insulin Resistance; Metabolic Syndrome; Middle Aged; Milk; Overweight; Oxidative Stress; Patient Dropouts; Republic of Korea; Risk Factors; Vascular Cell Adhesion Molecule-1

Leptin has nitric oxide (NO)-dependent vasodilator actions, but hyperleptinemia is an independent risk factor for cardiovascular disease.. The objective of the study was to investigate whether, in the human circulation, properties of leptin to release NO are opposed by stimulation of vasculotoxic substances, such as endothelin (ET)-1, and whether this mechanism might contribute to vascular damage in hyperleptinemic states like obesity.. Forearm blood flow responses (plethysmography) to ETA receptor antagonism (BQ-123, 10 nmol/min) and NO synthase inhibition [N(G)-monomethyl L-arginine (L-NMMA), 4 μmol/min] were assessed before and after intraarterial administration of leptin (2 μg/min) in lean controls (n = 8) and patients with obesity-related metabolic syndrome (MetS; n = 8).. Baseline plasma leptin was higher in patients than in controls (P < .001). Before infusion of leptin, the vasodilator response to BQ-123 was greater in patients than in controls (P < .001), whereas infusion of L-NMMA induced higher vasoconstriction in controls than in patients (P = .04). In lean subjects, hyperleptinemia resulted in increased vasodilator response to ETA receptor antagonism (P < .001 vs before) and enhanced vasoconstrictor effect of L-NMMA during ETA receptor blockade (P = .015 vs before). In patients with the MetS, by contrast, vascular responses to both BQ-123 and L-NMMA were not modified by exogenous leptin (both P > .05 vs before).. These findings indicate that, under physiological conditions, leptin stimulates both ET-1 and NO activity in the human circulation. This effect is absent in hyperleptinemic patients with the MetS who are unresponsive to additional leptin. In these patients, therefore, hyperleptinemia may be a biomarker of vascular dysfunction, rather than a mediator of vascular damage.

Topics: Adult; Antihypertensive Agents; Atherosclerosis; Endothelin A Receptor Antagonists; Endothelin-1; Enzyme Inhibitors; Female; Humans; Leptin; Male; Metabolic Syndrome; Middle Aged; Nitric Oxide; Nitric Oxide Synthase; Obesity; omega-N-Methylarginine; Peptides, Cyclic; Plethysmography; Receptor, Endothelin A; Risk Factors; Thinness; Vasodilation

Atherosclerosis is a chronic inflammatory disease of the arteries characterized by the accumulation of inflammatory cells in the arterial wall. Hypertension, dyslipidemia, and hyperglycemia are major risk factors of atherosclerosis. Rho-associated protein kinase (ROCK), a serine/threonine kinase, is a downstream effector of the small GTPase RhoA. ROCK is involved in different stages of atherosclerosis. Accumulating evidence has demonstrated that ROCK signaling plays vital roles in various cellular functions, such as contraction, migration, and proliferation of smooth muscle cells. Dysregulation of the ROCK pathway is associated with atherosclerosis and hypertension. Experimental studies have shown that ROCK inhibitors may have favorable effects in ameliorating atherosclerosis. ROCK signaling has a role in proteoglycan synthesis through transactivation of the TGF-β receptor Type I (TβRI) mediated by G-protein-coupled receptor (GPCR) agonists (endothelin-1, angiotensin II and …), and ROCK inhibitors could decrease proteoglycan synthesis and atherosclerotic plaque formation. Based on the hypothesis that targeting ROCK pathway may be effective in ameliorating atherosclerosis, we suggest that ROCK inhibitors may have a potential therapeutic role in inhibition or slowing atherogenesis. However, for this hypothesis more research is needed.

Topics: Angiotensin II; Atherosclerosis; Endothelin-1; Humans; Hypertension; Protein Serine-Threonine Kinases; Proteoglycans; Receptors, G-Protein-Coupled; rho-Associated Kinases; Serine

Atherosclerosis is a complex pathological process involving macrophages, endothelial cells and vascular smooth muscle cells that can lead to ischemic heart disease; however, the mechanisms underlying cell-to-cell communication in atherosclerosis are poorly understood. In this study, we focused on the role of exosomal miRNAs in crosstalk between macrophages and endothelial cells and explored the rarely studied molecular mechanisms involved. Our in vitro result showed that macrophage-derived exosomal miR-4532 significantly disrupted human umbilical vein endothelial cells (HUVECs) function by targeting SP1 and downstream NF-κB P65 activation. In turn, increased endothelin-1 (ET-1), intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and decreased endothelial nitric oxide synthase (eNOS) expression in HUVECs increased attraction of macrophages, exacerbating foam cell formation and transfer of exosomal miR-4532 to HUVECs. MiR-4532 overexpression significantly promoted endothelial injury and pretreatment with an inhibitor of miR-4532 or GW4869 (exosome inhibitor) could reverse this injury. In conclusion, our data reveal that exosomes have a critical role in crosstalk between HUVECs and macrophages. Further, exosomal miR-4532 transferred from macrophages to HUVECs and targeting specificity protein 1 (SP1) may be a novel therapeutic target in patients with atherosclerosis.

Topics: Atherosclerosis; Endothelin-1; Exosomes; Human Umbilical Vein Endothelial Cells; Humans; Intercellular Adhesion Molecule-1; Macrophages; MicroRNAs; NF-kappa B; Nitric Oxide Synthase Type III; Sp1 Transcription Factor; Transcription Factor RelA; Vascular Cell Adhesion Molecule-1

Zebrafish larvae were fed with high-cholesterol diet (HCD) to establish a zebrafish AS model. Then, we used DH water extracts (DHWE) to pretreat AS zebrafish. The plaque formation was detected by HE, EVG, and oil red O staining. Neutrophil and macrophage counts were calculated to evaluate the inflammation level. Reactive oxygen species (ROS) activity, malondialdehyde (MDA) content, and superoxide dismutase (SOD) activity in zebrafish were measured to reflect oxidative stress. The cholesterol accumulation and the levels of lipid, triglyceride (TG), and total cholesterol (TC) were measured to reflect lipid metabolism disorder. Then, parallel flow chamber was utilized to establish a low shear stress- (LSS-) induced endothelial cell (EC) dysfunction model. EA.hy926 cells were exposed to LSS (3 dyn/cm. The results showed that DHWE significantly reduced cholesterol accumulation and macrophage infiltration in early AS. Finally, DHWE significantly alleviate the lipid metabolism disorder, oxidative stress, and inflammation to reduce the plaque formation of AS zebrafish larval model. Meanwhile, we also found that DHWE significantly improved LSS-induced EC dysfunction and oxidative stress. Our results indicate that DHWE could be used as a prevention method to prevent AS.

Topics: Animals; Atherosclerosis; Cell Line; Cholesterol, Dietary; Dendrobium; Drugs, Chinese Herbal; Endothelin-1; Epoprostenol; Heart; Humans; Inflammation; Intercellular Adhesion Molecule-1; Nitric Oxide; Oxidative Stress; Reactive Oxygen Species; Shear Strength; Stress, Mechanical; Triglycerides; Umbilical Veins; Water; Zebrafish

NADPH oxidase (NOX) 1 but not NOX4-dependent oxidative stress plays a role in diabetic vascular disease, including atherosclerosis. Endothelin (ET)-1 has been implicated in diabetes-induced vascular complications. We showed that crossing mice overexpressing human ET-1 selectively in endothelium (eET-1) with apolipoprotein E knockout (Apoe-/-) mice enhanced high-fat diet-induced atherosclerosis in part by increasing oxidative stress. We tested the hypothesis that ET-1 overexpression in the endothelium would worsen atherosclerosis in type 1 diabetes through a mechanism involving NOX1 but not NOX4.. Six-week-old male Apoe-/- and eET-1/Apoe-/- mice with or without Nox1 (Nox1-/y) or Nox4 knockout (Nox4-/-) were injected intraperitoneally with either vehicle or streptozotocin (55 mg/kg/day) for 5 days to induce type 1 diabetes and were studied 14 weeks later. ET-1 overexpression increased 2.5-fold and five-fold the atherosclerotic lesion area in the aortic sinus and arch of diabetic Apoe-/- mice, respectively. Deletion of Nox1 reduced aortic arch plaque size by 60%; in contrast, Nox4 knockout increased lesion size by 1.5-fold. ET-1 overexpression decreased aortic sinus and arch plaque alpha smooth muscle cell content by ∼35% and ∼50%, respectively, which was blunted by Nox1 but not Nox4 knockout. Reactive oxygen species production was increased two-fold in aortic arch perivascular fat of diabetic eET-1/Apoe-/- and eET-1/Apoe-/-/Nox4-/- mice but not eET-1/Apoe-/-/Nox1y/- mice. ET-1 overexpression enhanced monocyte/macrophage and CD3+ T-cell infiltration ∼2.7-fold in the aortic arch perivascular fat of diabetic Apoe-/- mice. Both Nox1 and Nox4 knockout blunted CD3+ T-cell infiltration whereas only Nox1 knockout prevented the monocyte/macrophage infiltration in diabetic eET-1/Apoe-/- mice.. Endothelium ET-1 overexpression enhances the progression of atherosclerosis in type 1 diabetes, perivascular oxidative stress, and inflammation through NOX1.

Topics: Animals; Aorta; Atherosclerosis; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Endothelin-1; Endothelium, Vascular; Fibrosis; Humans; Macrophages; Mice, Inbred C57BL; Mice, Knockout, ApoE; Monocytes; NADPH Oxidase 1; Oxidative Stress; Plaque, Atherosclerotic; T-Lymphocytes; Up-Regulation

Knowledge on endothelial dysfunction and its relation to atherosclerosis in mastocytosis is limited.. To investigate the endothelial function in mastocytosis by flow-mediated dilatation (FMD) and biomarkers related to vascular endothelia and to evaluate its relationship with the presence of subclinical atherosclerosis by carotid intima media thickness (CIMT).. A total of 49 patients with mastocytosis and 25 healthy controls (HCs) were included. The FMD and CIMT during transthoracic echocardiography biomarkers including endocan, endothelin-1, and vascular endothelial growth factor (VEGF) were measured in the sera of participants. Tumor necrosis factor-alpha, interleukin 6, and high-sensitive C-reactive protein were determined as inflammatory biomarkers.. The mean FMD % was lower in the patients than HCs (11.26% ± 5.85% vs 17.84% ± 5.27% P < .001) and was the lowest in the advanced systemic mastocytosis and smoldering systemic mastocytosis group among the patients (P = .03). The median value of VEGF was considerably higher in patients than HCs (73.30 pg/mL; minimum-maximum 32.46-295.29 pg/mL vs 46.64 pg/mL; minimum-maximum, 11.09-99.86 pg/mL; P = .001) and it was the highest in the advanced systemic mastocytosis and smoldering systemic mastocytosis group (P = .01). The FMD was inversely correlated with endocan (r = -0.390; P = .006), endothelin-1 (r = -0.363; P = .01) and VEGF (r = -0.402; P = .004) but there were no correlations between FMD and tumor necrosis factor-alpha, interleukin 6, and high-sensitive C-reactive protein. No differences in CIMT values between patients and HCs and no correlation between CIMT and the biomarkers were observed.. Endothelial dysfunction in mastocytosis becomes evident with decreased FMD and elevated serum VEGF in the absence of atherosclerosis or systemic inflammation and is related to disease severity.

Topics: Adult; Atherosclerosis; Biomarkers; Carotid Intima-Media Thickness; Case-Control Studies; Endothelin-1; Endothelium, Vascular; Female; Humans; Inflammation; Male; Mastocytosis; Middle Aged; Neoplasm Proteins; Proteoglycans; ROC Curve; Severity of Illness Index; Vascular Endothelial Growth Factor A; Vasodilation

Air pollution increases the morbidity and mortality of cardiovascular disease (CVD). Atherosclerosis (AS) is the pathological basis of most CVD, and the progression of atherosclerosis and the increase of fragile plaque rupture are the mechanism basis of the relationship between atmospheric particulate pollution and CVD. The aim of the present study was to investigate the effects of coal-fired fine particulate matter (PM. Different concentrations of PM. Coal-fired PM. Coal-derived PM

Topics: Air Pollutants; Animals; Aorta; Atherosclerosis; Coal; E-Selectin; Endothelin-1; Intercellular Adhesion Molecule-1; Male; Mice, Knockout, ApoE; Mitogen-Activated Protein Kinases; Particulate Matter; Phosphorylation; Power Plants

Atherosclerosis is a chronic inflammatory disease triggered by endothelial dysfunction and exaggerated by macrophage infiltration. Although endothelin-1 (ET-1) plays an important role in vascular inflammation and reactive oxygen species production, the individual effect of ET-1 in atherogenesis remains unclear.. ET-1 expression was increased in mouse atherosclerotic plaques and human umbilical vein endothelial cells (HUVECs) administrated by oxidized low-density lipoprotein stimulation. Moreover, the immunofluorescence co-staining showed upregulated ET-1 expression in endothelial cells. Real-time polymerase chain reaction demonstrated that ET-1 overexpression promoted adhesion molecules and chemokines secretion in HUVECs. Following this intervention, the migration of macrophages and the pro-inflammatory cytokines were increased. More importantly, the endothelial dysfunction regulated by ET-1 and subsequently the effect on macrophage activation were mediated by ETA receptor and largely reversed by protein kinase C (PKC) inhibitor. Eight-week-old male ApoE-/- mice and eET-1/ApoE-/- mice were fed with high-fat diet for 12 weeks. eET-1/ApoE-/- significantly increased atherosclerotic lesions in the whole aorta and aortic sinus, which accompanied by the induction of inflammatory cytokines and macrophages infiltration.. ET-1 accelerates atherogenesis by promoting adhesion molecules and chemokines, as well as subsequent macrophage activation. Collected, these evidence suggest that ET-1 might be a potential target for the treatment of atherogenesis.

Topics: Animals; Atherosclerosis; Cell Adhesion Molecules; Cell Movement; Cytokines; Disease Models, Animal; Endothelial Cells; Endothelin-1; Human Umbilical Vein Endothelial Cells; Humans; Inflammation Mediators; Macrophage Activation; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout, ApoE; Paracrine Communication; Plaque, Atherosclerotic; Protein Kinase C; RAW 264.7 Cells; Receptor, Endothelin A; Signal Transduction

Topics: Atherosclerosis; Endothelial Cells; Endothelin Receptor Antagonists; Endothelin-1; Humans; Macrophage Activation

All-trans retinoic acid (ATRA) is a natural derivative of vitamin A that ameliorates atherosclerosis (AS) by regulating inflammatory factors. However, studies concerning the role of retinoic acid in artery endothelial function are rare. Therefore, the present study investigated its role in regulating the production of endothelin‑1 (ET‑1) and nitric oxide (NO) in rabbits with AS. The rabbits were randomly divided into 3 groups: The control group was administered an ordinary diet, while the high fat group and the ATRA drug intervention group were administered a high fat diet. After 12 weeks, the blood lipid levels of rabbits, the morphological structure of the arterial wall, the arterial intimal permeability, the activity of blood endothelial nitric oxide synthase (eNOS) and the level of plasma NO were investigated. Western blot analysis was used to detect the levels of ET‑1, eNOS and eNOS phosphorylation at Ser‑1177 (p‑eNOS), and a radioimmunoassay was performed to detect the level of ET‑1 in the plasma. It was identified that plaque formation was alleviated in the ATRA group compared with the high fat group, as revealed by hematoxylin and eosin and oil red O staining, and a similar trend was reflected in the immunofluorescence results for endothelial permeability. Western blotting demonstrated significantly decreased ET‑1 expression levels in the arterial tissue of rabbits in the ATRA group compared with the high fat group, together with increased p‑eNOS level (P<0.05), however, no difference was observed in the expression of eNOS (P>0.05). The trends observed for ET‑1 and the activity of eNOS in plasma were similar to those for arterial tissue. Therefore, the present study demonstrated that ATRA may regulate the grade of AS by the reduction of ET‑1 secretion and increased NO formation via increased phosphorylation of eNOS. ATRA provides a potential novel method for the treatment of atherosclerosis.

Topics: Animals; Atherosclerosis; Cell Membrane Permeability; Endothelial Cells; Endothelin-1; Gene Expression Regulation; Male; Nitric Oxide; Nitric Oxide Synthase Type III; Phosphorylation; Plaque, Atherosclerotic; Rabbits; Tretinoin

Oxidative stress and inflammation are associated with endothelial injury and coronary artery disease. Inflammatory factors that promote oxidative damage include endothelin-1 (ET-1), myeloperoxidase (MPO), and C-reactive protein (CRP). Current guidelines recommend the use of statins in patients with risk of atherosclerotic cardiovascular disease (ASCVD).. To assess the impact of atorvastatin on plasma inflammatory and oxidant biomarkers in patients with moderate to very high risk of ASCVD.. Two hundred ten patients presented to the cardiology clinic were included and stratified into low, moderate, high, and very high risk of ASCVD. Moderate- (20 mg/d) to high-intensity (40 mg/d) atorvastatin was prescribed. Plasma levels of lipids, ET-1, CRP, MPO, total nitrite, lipid peroxides (thiobarbituric acid reactive substances [TBARS]), and superoxide dismutase (SOD) activities were measured at baseline and 12 weeks after treatment.. Relative to low-risk patients, baseline plasma inflammatory markers of CRP, MPO, ET-1, and nitrite were higher in patients with very high risk of ASCVD, whereas plasma SOD was lower (all P < .05). Use of high and moderate atorvastatin therapy significantly reduced low-density lipoprotein and total cholesterol levels, as well as plasma levels of CRP, MPO, nitrite, and TBARS, and increased plasma SOD activity in patients with moderate to very high risk of ASCVD, independent of lipid-lowering effects.. Key markers of oxidative stress/inflammation such as CRP, ET-1, total nitrite, and MPO are associated with an increased risk of ASCVD. Moderate- and high-intensity atorvastatin use reduces plasma oxidative stress and inflammation regardless of ASCVD risk and independent of its lipid-lowering effect.

Topics: Adult; Aged; Atherosclerosis; Atorvastatin; C-Reactive Protein; Dose-Response Relationship, Drug; Endothelin-1; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Lipids; Male; Middle Aged; Oxidants; Oxidative Stress; Peroxidase; Prospective Studies; Risk Factors; Superoxide Dismutase

Progression of coronary artery calcification (CAC) was significantly associated with all-cause mortality, and high coronary artery calcium score (CACS) portends a particularly high risk of cardiovascular events. But how often one should rescan is still an unanswered question. Preliminary screening by testing circulating biomarker may be an alternative before repeat computed tomography (CT) scan. The aim of this study was to investigate the value of big endothelin-1 (bigET-1), the precursor of endothelin-1 (ET-1), in predicting the severity of CAC. A total of 428 consecutively patients who performed coronary computed tomography angiography (CCTA) due to chest pain in Fuwai Hospital were included in the study. The clinical characteristics, CACS, and laboratory data were collected, and plasma bigET-1 was detected by enzyme-linked immunosorbent assay (ELISA). The bigET-1 was positively correlated with the CACS ( r = .232, P < .001), and the prevalence of CACS >400 increased significantly in the highest bigET-1 tertile than the lowest tertile. Multivariate analysis showed that bigET-1was the independent predictor of the presence of CACS >400 (odds ratio [OR] = 1.721, 95% confidence interval [CI], 1.002-2.956, P = .049). The receiver operating characteristic (ROC) curve analysis showed that the optimal cutoff value of bigET-1 for predicting CACS >400 was 0.38 pmol/L, with a sensitivity of 59% and specificity of 68% (area under curve [AUC] = 0.65, 95% CI, 0.58-0.72, P < .001). The present study demonstrated that the circulating bigET-1 was valuable in the assessment of the severity of CAC.

Topics: Atherosclerosis; Coronary Artery Disease; Coronary Vessels; Endothelin-1; Female; Humans; Male; Middle Aged; Risk Factors; Vascular Calcification

As an initial step in exploring the feasibility of oral sulfhydryl as an adjuvant for improving nitrate ester tolerance, this study was designed to experimentally test the adjuvant therapy in a rabbit model of atherosclerosis (AS).. New Zealand white rabbits with induced AS were randomly divided into four groups: AS group, AS + nitrate ester group, AS + nitrate ester tolerance group, and AS + drug combination group. Additionally, four equivalent groups with healthy New Zealand white rabbits without AS were also conformed. After feeding the animals for 5 days, the concentrations of superoxide anion (•O2-), superoxide dismutase (SOD), malondialdehyde (MDA), nitric oxide (NO), and endothelin-1 (ET-1) in blood and the relaxation response of the aortic ring were determined in each subject. The vascular plaques in different treatment groups were assessed by Hematoxylin and eosin (HE) staining to investigate the therapeutic value of sulfhydryl as coadjuvant for improving nitrate ester tolerance, and changes in blood vessels in different treatment groups were studied by immunohistochemical assays.. Our results showed no significant differences through time in the concentrations of •O2-, SOD, MDA, NO, ET-1 between the healthy control and the nitrate ester groups (p > 0.05). The levels of SOD and MDA in the nitrate ester tolerance group increased with time, however, the levels of •O2-, NO and ET-1 decreased gradually (p < 0.05). The NO, •O2- and ET-1 levels in both the AS and AS + nitrate ester tolerance groups were significantly decreased, but SOD and MDA were significantly increased (p < 0.05). SOD and MDA in the AS + nitrate ester group decreased gradually with time, but •O2-, NO- and ET-1 levels increased (p < 0.05). The levels of SOD and MDA in the AS + drug combination and the drug combination group decreased significantly with time, in contrast, those of •O2-, NO- and ET-1 increased (p < 0.05). The results of HE staining proved that the atherosclerosis model was established successfully.. We conclude the use of a sulfhydryl compound as an adjuvant significantly reduced nitrate ester tolerance, and this strategy was safe and looks promising for humans.

Topics: Administration, Oral; Animals; Atherosclerosis; Drug Tolerance; Endothelin-1; Female; Isosorbide Dinitrate; Male; Models, Animal; Nitric Oxide; Rabbits; Sulfhydryl Compounds; Superoxide Dismutase; Superoxides; Vasodilator Agents

We compared the expression of signal molecules in the culture of human endothelial cells under normal conditions and in atherosclerosis and restenosis. Expression of connexin-37 and sirtuin-1 in atherosclerosis and restenosis surpassed the normal by 2 and 5 times, respectively, and expression of endothelin-1 3-fold surpassed the normal. In restenosis, changes in the expression connexin-37 and endothelin-1 became more pronounced in comparison with atherosclerosis. Connexin-37 and endothelin-1 can serve as predictive markers for prognosis of post-stenting complications in patients with atherosclerosis.

Topics: Atherosclerosis; Cells, Cultured; Connexins; Coronary Restenosis; Endothelial Cells; Endothelin-1; Humans

Recent research has shown that hypovitaminosis D may increase the risk of hypertension, vascular disease, diabetes mellitus, obesity and Metabolic Syndrome (MetS). Endothelial Dysfunction (ED) is one of the key components of MetS which is associated with an imbalance between vasoactive substances such as Nitric Oxide (NO) and Endothelins (ET). In this study, we assessed the association of 25(OH) D3 level with endothelial dysfunction and subclinical atherosclerosis in MetS patients.. 105 MetS patients and 48 controls were included. 25(OH) D3 levels were measured using Ultra-High Performance Liquid Chromatography (UHPLC). NOx (NO2 plus NO3) and Endothelin- 1(ET-1) concentrations were determined along with routine biochemical tests. Flow-Mediated Dilatation (FMD) and carotid Intima-Media Thickness (cIMT) were measured by ultrasonography.. In MetS patients, vitamin D and NOx levels were significantly lower (p<0.001), while ET-1 levels were higher than controls (p<0.005). MetS patients with ED exhibited significantly lower vitamin D levels than their counterparts free of ED. Vitamin D levels were correlated positively with FMD and NOx, and negatively with systolic blood pressure and body mass index. Subclinical atherosclerosis as assessed by the cIMT did not associate with low vitamin D levels.. Vitamin D deficiency seen in MetS patients is more prominent in the presence of ED. Hypovitaminosis D may affect endothelial cells, and participate in the development of hypertension.

Topics: Adult; Asymptomatic Diseases; Atherosclerosis; Biomarkers; Calcifediol; Carotid Intima-Media Thickness; Case-Control Studies; Chromatography, High Pressure Liquid; Endothelin-1; Endothelium, Vascular; Female; Humans; Male; Metabolic Syndrome; Middle Aged; Nitrates; Nitrites; Prognosis; Risk Factors; Vasodilation; Vitamin D Deficiency

Atherosclerosis is an important predictor of mortality in patients with chronic kidney disease (CKD) and is associated with a wide inflammatory response. The aim of this study is to evaluate in vitro how different membranes can remove mediators associated with this pathology in a closed loop dialysis model. We performed experimental hemofiltration in vitro using three different membrane materials. Human plasma was preliminarily incubated with various inflammatory mediators and filtered in a closed loop circulation model for 240 min. Respective concentrations of 17 different mediators were measured over time to study the removal mechanisms of each membrane, including associated removal time course. The experiment was repeated three times for the assay of tumor necrosis factor (TNF)-α to document the model variability. Means were compared using Mann-Whitney test. Most of the investigated mediators were effectively removed with the different dialysis membranes. Adsorption mechanism was mainly at the origin of the decrease in mediators circulating concentrations and was maximized in the region 10 000-20 000 Da. Especially, the HeprAN membrane showed fast removal capacities of mediators with elevated isoelectric point including complement factors and chemokines or having basic groups located in the protein periphery, plasminogen activator inhibitor (PAI-1), and TNF-α-like. The latter was further significantly removed with HeprAN and polymethylmethacrylate (PMMA) compared to polyethersulfone (PES) material (P < 0.01). We concluded that dialysis using ionic adsorptive membrane could have a beneficial impact for CKD patients with atherosclerosis and would deserve further clinical investigations.

Topics: Adsorption; Atherosclerosis; Chemokine CCL2; Endothelin-1; Equipment Design; Hemofiltration; Humans; Inflammation; Inflammation Mediators; Membranes, Artificial; Pilot Projects; Plasminogen Activator Inhibitor 1; Polymers; Polymethyl Methacrylate; Renal Insufficiency, Chronic; Sulfones; Tumor Necrosis Factor-alpha

Peptide KED (Lys-Glu-Asp) has vasoprotective effects and is effective substance in treatment of of atherosclerosis and other cardio-vascular disorders in elderly people. One of the probable mechanisms of biological activity of this peptide is epigenetic genes regulation. These genes can coding proteins, which are markers of endothelium functional activity. The goal of investigation was to study the KED peptide effect on signal molecules expression in normal, atherosclerotic and restenotic endothelium in vitro. It was shown, that KED peptide has normalized endothelin-1 expression, which increased during atherosclerosis and restenosis. KED peptide also restorates cells interactions by connexin expression. Geroprotective effect of KED peptide is realized by increasing of sirtuin1 expression, which has took part in DNA reparation.. Пептид KED (Lys-Glu-Asp) обладает выраженными вазопротекторными свойствами и является эффективным средством в терапии атеросклероза и другой патологии сердечно-сосудистой системы у людей пожилого возраста. Одним из возможных механизмов действия пептида KED является эпигенетическая регуляция экспрессии генов, кодирующих белки-маркеры функциональной активности эндотелия. Целью работы явилось изучение влияния пептида KED на экспрессию сигнальных молекул в эндотелии сосудов in vitro в норме, при атеросклерозе и рестенозе. Установлено, что пептид KED нормализует повышенную при атеросклерозе экспрессию эндотелина-1 и восстанавливает межклеточные взаимодействия эндотелиоцитов, осуществляемые коннексинами. Геропротекторное влияние пептида KED на эндотелий реализуется в повышении экспрессии сиртуина-1, белка, участвующего в репарации ДНК.

Topics: Aorta; Atherosclerosis; Endothelin-1; Endothelium, Vascular; Epigenesis, Genetic; Gene Expression Regulation; Humans; Oligopeptides; Pharmacogenetics; Protective Agents

Both altered shear rate and endothelin-1 (ET-1) are associated with the age-related development of atherosclerosis. However, the role of ET-1, a potent endogenous vasoconstrictor, in altering shear rate in humans, especially in the atherosclerotic-prone vasculature of the leg, is unknown. Therefore, this study examined the contribution of ET-1 to the age-related alterations in common femoral artery (CFA) shear rate.. BQ-123, a specific endothelin type A (ET(A)) receptor antagonist, was infused into the CFA, and diameter and blood velocity were measured by Doppler ultrasound in young (n = 8, 24 ± 2 years) and old (n = 9, 70 ± 2 years) study participants.. The old had greater intima-media thickening in the CFA, indicative of a preatherogenic phenotype. Prior to infusion, the old study participants exhibited reduced mean shear rate (27 ± 3/s) compared with the young study participants (62 ± 9/s). This difference was likely driven by attenuated antegrade shear rate in the old as retrograde shear rate was similar in the young and old. Inhibition of ETA receptors, by BQ-123, increased leg blood flow in the old, but not in the young, abolishing age-related differences. Older study participants had a larger CFA (young: 0.82 ± 0.03 cm, old: 0.99 ± 0.03 cm) in which BQ-123 induced significant vasodilation (5.1 ± 1.0%), but had no such effect in the young (-0.8 ± 0.8%). Interestingly, despite the age-specific, BQ-123-induced increase in leg blood flow and CFA diameter, shear rate patterns remained largely unchanged. Therefore, ET-1, acting through the ETA receptors, exerts a powerful age-specific vasoconstriction. However, removal of this vasoconstrictor stimulus does not augment mean shear rate in the old.

Topics: Adult; Age Factors; Aged; Atherosclerosis; Blood Flow Velocity; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Femoral Artery; Hemodynamics; Humans; Peptides, Cyclic; Ultrasonography, Doppler; Vasodilation; Young Adult

Recent studies in type 2 diabetes have reported an association between hypoglycemia and severe cardiovascular adverse events, which are relatively increased in standard versus intensively treated individuals. The aim of this study was to determine the effects of equivalent sympathetic nervous system (SNS) activity during moderate hypoglycemia on in-vivo endothelial function, pro-inflammatory, pro-atherothrombotic, and pro-coagulant responses in healthy and standard treated type 2 diabetes individuals.. Eleven type 2 diabetes and 16 healthy individuals participated in single 2day studies. Day 1 involved a 2h hyperinsulinemic/euglycemic clamp and day 2, a 2h hyperinsulinemic/hypoglycemic clamp of 3.2±1mmol/L in type 2 diabetes and (2.9±0.1mmol/L) in healthy individuals.. ICAM-1, VCAM-1, P-selectin, PAI-1, VEGF and endothelin-1 (ET-1) fell during hyperinsulinemic euglycemia but increased during hypoglycemia in type 2 diabetes and healthy individuals. Epinephrine and norepinephrine levels were equivalent during hypoglycemia in type 2 DM and healthy individuals. However, despite similar SNS drive but milder and hypoglycemia there were greater ICAM-1, VCAM-1, PAI-1, VEGF and ET-1 responses in the type 2 diabetes group. Endogenous and exogenous nitric oxide mediated arterial vasodilation were also impaired only during hypoglycemia in type 2 diabetes.. We conclude that, milder hypoglycemia but equivalent SNS activation results in more diffuse endothelial dysfunction and a greater pro-inflammatory, pro-atherothrombotic and pro-coagulant state in standard treated type 2 diabetes as compared to healthy individuals.

Topics: Adult; Atherosclerosis; Blood Coagulation; Case-Control Studies; Diabetes Mellitus, Type 2; Endothelin-1; Endothelium, Vascular; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Inflammation; Intercellular Adhesion Molecule-1; Male; Middle Aged; Obesity; P-Selectin; Plasminogen Activator Inhibitor 1; Sympathetic Nervous System; Vascular Cell Adhesion Molecule-1; Vascular Endothelial Growth Factor A

Micro and macrovascular complications occurring during hyperlipidemia are mostly attributed to haemostatic impairment and vascular endothelial dysfunction. Cholesteryl ester transfer protein (CETP) inhibitors have been emerged recently as promising hypocholesterolemic agents to confer protection against lipid-mediated atherosclerosis. Therefore, 10-dehydrogingerdione (DHGD), a novel CETP inhibitor isolated from ginger rhizomes, was selected as a natural product in the present study to illustrate its effect on haemostatic impairment associated with hyperlipidemia as compared to a currently used hypocholesterolemic agent, atorvastatin (ATOR). Rabbits were fed a high cholesterol diet (HCD) and divided into three groups. One group served as control group while the other groups received DHGD or ATOR. Dyslipidemic rabbits showed a significant increase in serum endothelin-1, ischemia modified albumin, plasminogen activator inhibitor-1, prothrombin fragments (1+2) and plasma fibrinogen along with a decrease of nitric oxide level in serum. Daily administration of ATOR or DHGD significantly decreased the aforementioned coagulation and ischemia biomarkers and increased serum nitric oxide. DHGD (natural) results seem to be more remarkable as compared to ATOR (synthetic).

Topics: Animals; Anticholesteremic Agents; Atherosclerosis; Atorvastatin; Blood Coagulation; Cholesterol Ester Transfer Proteins; Disease Models, Animal; Dyslipidemias; Endothelin-1; Endothelium, Vascular; Guaiacol; Nitric Oxide; Plasminogen Activator Inhibitor 1; Rabbits; Treatment Outcome

Endothelin-1 (ET-1) is known as potent vasoconstrictor, by virtue of its mitogenic effects, and may deteriorate the process of hypertension and atherosclerosis by aggravating hyperplasia and migration in VSMCs. Our previous study demonstrated that insulin infusion caused sequential induction of hyperinsulinemia, hyperendothelinemia, insulin resistance, and then hypertension in rats. However, the underlying mechanism of ET-1 interfere insulin signaling in VSMCs remains unclear. To characterize insulin signaling during modest insulin resistant syndrome, we established and monitored rats by feeding high fructose-diet (HFD) until high blood pressure and modest insulin resistance occurred. To explore the role of ET-1/ETAR during insulin resistance, ETAR expression, ET-1 binding, and insulin signaling were investigated in the HFD-fed rats and cultured A-10 VSMCs. Results showed that high blood pressure, tunica medial wall thickening, plasma ET-1 and insulin, and accompanied with modest insulin resistance without overweight and hyperglycemia occurred in early-stage HFD-fed rats. In the endothelium-denuded aorta from HFD-fed rats, ETAR expression, but not ETBR, and ET-1 binding in aorta were increased. Moreover, decreasing of insulin-induced Akt phosphorylation and increasing of insulin-induced ERK phosphorylation were observed in aorta during modest insulin resistance. Interestingly, in ET-1 pretreated VSMCs, the increment of insulin-induced Akt phosphorylation was decreased whereas the increment of insulin-induced ERK phosphorylation was increased. In addition, insulin potentiated ET-1-induced VSMCs migration and proliferation due to increasing ET-1 binding. ETAR antagonist reversed effects of ET-1 on insulin-induced signaling and VSMCs migration and proliferation. In summary, modest insulin resistance syndrome accompanied with hyperinsulinemia leading to the potentiation on ET-1-induced actions in aortic VSMCs. ET-1 via ETAR pathway suppressed insulin-induced AKT activation, whereas remained insulin-induced ERK activation. ET-1 and insulin synergistically potentiated migration and proliferation mainly through ETAR/ERK dependent pathway, which is dominant in VSMCs during modest insulin resistance syndrome. Therefore, ET-1 and ETAR are potential targets responsible for the observed synergism effect in the hypertensive atherosclerotic process through enhancement of ET-1 binding, ET-1 binding, ETAR expression, and ET-1-induced mitogenic actions in aortic VSMCs.

Topics: Animals; Atherosclerosis; Cells, Cultured; Diet, High-Fat; Disease Models, Animal; Endothelin-1; Hypertension; Insulin; Insulin Resistance; Muscle, Smooth, Vascular; Phosphorylation; Rats; Rats, Sprague-Dawley

Vascular endothelial dysfunction and inflammatory response are early events during initiation and progression of atherosclerosis. In vitro studies have described that CIT markedly upregulates expressions of ICAM-1 and VCAM-1 of endothelial cells, which result from NF-κB activation induced by CIT. In order to determine whether it plays a role in atherogenesis in vivo, we conducted the study to investigate the effects of CIT on atherosclerotic plaque development and inflammatory response in apolipoprotein E deficient (apoE-/-) mice. Five-week-old apoE-/- mice were fed high-fat diets and treated with CIT for 15 weeks, followed by assay of atherosclerotic lesions. Nitric oxide (NO), vascular endothelial growth factor (VEGF) and endothelin-1 (ET-1) were detected in serum. Levels of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), VEGF, and ET-1 in plaque areas of artery walls were examined. NF-κB p65 expression and NF-κB activation in aorta also were assessed. CIT treatment significantly augmented atherosclerotic plaques and increased expressions of ICAM-1, VCAM-1, VEGF and ET-1 in aorta. Mechanistic studies showed that activation of NF-κB was significantly elevated by CIT treatment, indicating the effect of CIT on atherosclerosis may be regulated by activation of NF-κB.

Topics: Animals; Aorta; Apolipoproteins E; Atherosclerosis; Aurovertins; Body Weight; Diet, High-Fat; Endothelin-1; Endothelium, Vascular; Hypercholesterolemia; Inflammation; Intercellular Adhesion Molecule-1; Lipids; Male; Mice, Inbred C57BL; NF-kappa B; Nitric Oxide; Up-Regulation; Vascular Cell Adhesion Molecule-1; Vascular Endothelial Growth Factor A

We investigated the therapeutic effect of Xin Mai Jia (XMJ) on atherosclerosis (AS) in rats. Rat models of AS were established by peritoneally injecting vitamin D, feeding a high-fat diet, and inducing balloon injuries in rats. The stomachs of the rats were irrigated continuously for 10 weeks with XMJ. Blood lipid- and hemorheology-related indices of blood samples were detected. Pathological changes in the right common carotid arterial tissues were also determined. The protein expression levels of endothelial nitric oxide synthase, angio-tensin-1, and endothelin-1 were determined by western blotting. XMJ reduced cholesterol, trigylecride, and low-density lipoprotein levels as well as blood viscosity, sedimentation, and hematocrit. Furthermore, XMJ alleviated vascular endothelial injury and reduced/eliminated atherosclerotic plaques. In contrast, XMJ significantly increased the endothelium-dependent relaxing response of the AS rat models. The western blotting results showed that XMJ upregulated endothelial nitric oxide synthase but downregulated angiotensin-1 and endothelin-1. XMJ prevented the development of AS by regulating blood lipid levels, hemorheology, and vascular function.

Topics: Angiotensins; Animals; Atherosclerosis; Cholesterol; Diet, High-Fat; Endothelin-1; Endothelium, Vascular; Gene Expression; Humans; Lipoproteins, LDL; Male; Medicine, Chinese Traditional; Nitric Oxide; Nitric Oxide Synthase Type III; Rats; Vitamin D

To examine the effect of H2S donor, sodium hydrosulfide (NaHS), on ET-1 level in plasma and aorta in rats with atherosclerosis (AS).. Thirty male rats, weighting 200-220 g, were randomly divided into AS, AS+NaHS and control groups, n = 10 in each group.Rats were given a single dose of vitamin D3 (700 000 U/kg) in the first three days and fed with a high-cholesterol diet for 8 weeks to induce AS. Rats in AS+NaHS group were intraperitoneally injected with an H2S donor NaHS, at a dose of 56 µmol/(kg·d) for 8 weeks. At the end of the experiment for 8 weeks, all the rats were sacrificed. The plasma was collected and the aorta and coronary tissues were isolated. The atherosclerotic lesions in both aorta and coronary arteries were detected using oil red O method. H2S concentration in plasma was determined with sulfide-sensitive electrode method. ET-1 levels in plasma and aorta were calculated by radioimmunoassay kit and the localization of ET-1 in the aorta was detected by immunohistochemistry. Plasma nitric oxide synthase (NOS), endothelial NOS (eNOS), inducible NOS (iNOS) were detected with colorimetry.. AS plaque area in root of aorta of rats in AS group, AS+NaHS group and control group were (11.6±3.3)%, (1.6±1.1)%, (0.0±0.1)% respectively. The difference in AS plaque area in root of aorta among the three groups was statistically significant (F=97.675, P < 0.05). AS plaque area in coronary artery of rats in AS group, AS+NaHS group and control group were (21.4±5.7)%, (4.8±2.5)%, (0.0±0.0)% respectively. The difference in AS plaque area in coronary artery among the three groups was statistically significant (F=97.519, P < 0.05). Plasma H2S level in rats of AS group ((22.0±3.1) µmol/L) was significantly lower than that of control group ((27.9±1.0) µmol/L) and AS+NaHS group ((33.3±6.2) µmol/L, all P < 0.05). Compared with control group ((70.0±10.7) ng/L), plasma ET-1 in rats of AS group ((89.6±14.2) ng/L) and AS+NaHS group ((93.1±15.5) ng/L, P both < 0.05) were increased. However, there was no significant difference in plasma ET-1 content in rats between AS+NaHS group and AS group (P > 0.05). Compared with control group ((3.8±1.2) ng/g), ET-1 content in aorta in rats of AS group ((11.9±4.9) ng/g) and AS+NaHS group ((8.2±2.5) ng/g, both P < 0.05) were increased, and ET-1 content in aorta in rats of AS+NaHS group was decreased compared with AS group (P < 0.05). Immunochemistry results showed that ET expression in cytoplasm in aortic endothelial cells in rats of AS group was strengthened, while ET expression in rats of control group and AS+NaHS group was weak. NOS activity of rats in control group, AS group and AS+NaHS group was (25.4±5.6), (51.8±10.0) and (27.6±6.5) U/ml, eNOS activity (15.3±6.2), (4.5±2.7) and (8.7±3.9) U/ml, and iNOS activity (9.9±4.0), (47.3±10.7) and (19.0±5.2) U/ml, respectively.Differences among the three groups were statistically significant (NOS activity: F=37.231, P < 0.05, eNOS activity: F=14.600, P < 0.05, and iNOS activity: F=72.131, P < 0.05).. H2S donor NaHS reduced the AS plaque in AS rats. The mechanisms might involve the protective effect of H2S on the vascular endothelial cell, decreasing ET-1 production in aortal endothelium of atherosclerotic rats.

Topics: Animals; Aorta; Atherosclerosis; Coronary Vessels; Disease Models, Animal; Endothelin-1; Hydrogen Sulfide; Male; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Random Allocation; Rats; Sulfides

To evaluate the association of obstructive sleep apnea hypopnea syndrome (OSAHS) with carotid atherosclerosis and the efficacy of continuous positive airway pressure (CPAP) treatment.. A total of 93 OSAHS patients diagnosed by polysomnography (PSG) were selected from Sleep Disorders Center at Affiliated Hospital of Xuzhou Medical College between March 2013 and December 2014. Based on the results of apnea-hypopnea index (AHI), they were divided into mild (n=22), moderate (n=37), and severe OSAHS group (n=34). Meanwhile, 28 healthy adult individuals matched for age and body mass index (BMI) were enrolled as the control group. The carotid intima-mesa thickness (IMT) was measured by color Doppler uhrasonography, and plasma levels of tumor necrosis factor-α (TNF-α), endothelin-1 (ET-1) and nitric oxide (NO) were determined by Enzyme-Linked Immunosorbent Assay (ELISA). The correlations between carotid IMT and plasma levels of TNF-α, ET-1 and NO were analyzed. A total of 24 patients with moderate to severe OSAHS underwent CPAP treatment and the carotid IMT, plasma levels of TNF-α, ET-1 and NO were compared before and after CPAP treatment.. OSAHS patients had significant increase of carotid IMT with the increasing disease severity, and the carotid IMT in mild, moderate and severe OSAHS groups were all significantly higher than that in the control group ((0.73 ± 0.31), (0.86 ± 0.07), (1.07 ± 0.14) vs (0.65 ± 0.10) mm, all P<0.05). The plasma levels of TNF-α and ET-1 in mild to severe OSAHS group were significantly higher than those in controls ((17.45 ± 3.02), (23.81 ± 2.91), (35.16 ± 3.43) vs (12.53 ± 3.48) ng/L and (0.81 ± 0.13), (1.06 ± 0.21), (1.66 ± 0.30) vs (0.64 ± 0.12) ng/L, all P<0.05 ), whereas plasma levels of NO in the three OSAHS groups were significantly decreased compared with the control group ((35.46 ± 10.12), (29.32 ± 9.47), (20.16 ± 7.41) vs (45.43 ± 7.92) µmol/L, all P<0.05). Furthermore, there were significant differences in plasma levels of TNF-α, ET-1 and NO among the three OSAHS groups (all P<0.05). Carotid IMT was positively correlated with plasma TNF-α and ET-1 (r=0.56 and 0.51) and negatively correlated with plasma NO (r=-0.46) (all P<0.05). After 3 months of CPAP treatment, plasma levels of TNF-α and ET-1 in OSAHS patients were significantly reduced ((19.64 ± 5.28), (0.94 ± 0.21) vs (28.72 ± 5.36), (1.36 ± 0.36) ng/L), and plasma NO was markedly increased ((33.57 ± 6.32) vs (24.34 ± 4.46) µmol/L, all P<0.05). However, CPAP treatment did not have a significant effect on carotid IMT ((0.91 ± 0.21) vs (0.96 ± 0.14) mm), P>0.05).. Systemic inflammation and vascular endothelial dysfunction may play an important role in pathogenesis and development of carotid artery atherosclerosis in OSAHS. Short-term CPAP therapy alleviates systemic inflammation and improves endothelial function, but does not influence the increased carotid IMT in OSAHS patients.

Topics: Atherosclerosis; Body Mass Index; Carotid Artery Diseases; Continuous Positive Airway Pressure; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Humans; Inflammation; Nitric Oxide; Polysomnography; Sleep Apnea, Obstructive; Tumor Necrosis Factor-alpha; Tunica Intima

It is now widely accepted that the microcirculation plays a role in the complications of atherosclerosis, but the microcirculation response to atherosclerosis risk factors like diabetes, hypercholesterolemia and hypertension, is still unclear. Alterations in the endothelial production of IL6, NO and ET-1 are known to be correlate with these diseases. Simulating the presence of hyperglycemia, hypercholesterolemia and hypertension, this in vitro study investigated the effect of glucose, angiotensin II, and nLDL treatments on IL-6, ET-1 and NO in HMEC-1. The medium concentrations of IL6 and ET-1 were measured by ELISA assay, whereas NO by a colorimetric assay. The mRNA and protein expressions of IL-6, Pre-po-ET-1 and eNOS by extracted cells were also investigated by RT-PCR. NO concentration in the medium of HMEC-1 increased in a dose-dependent manner by glucose after 24 hours and by nLDL both at 6 and 24 h, with higher values at 6 hours. The eNOS mRNA expression at 6h induced by nLDL, showed a parallel trend to the medium NO. No increment dose dependent NO concentration was observed by angiotensin II.nLDL induced a dose-dependent increase of ET-1 medium levels, more accentuated in 6h respect to 24h. The expression of prepro-ET-1 showed a parallel dose-dependent increased after 6 hours. Both glucose and nLDL increased IL-6 levels in a dose-dependent manner at 6 and 24 h. In conclusion, glucose treatment on HMEC-1 cells exerted a mild stimulus on NO and IL-6 production. nLDL treatment showed a similar glucose stimulus on NOx, but it induced an intense pro-inflammatory activity and showed the ability to stimulate ET-1 synthesis.

Topics: Angiotensin II; Atherosclerosis; Blood Glucose; Cell Line; Cholesterol, LDL; Endothelin-1; Endothelium, Vascular; Healthy Volunteers; Humans; Interleukin-6; Microcirculation; Nitric Oxide; Nitric Oxide Synthase Type III

Toll-like receptor 4 (TLR4)-tumor necrosis factor receptor 6 (TRAF6) signaling is activated in atherosclerosis (AS), inducing inflammatory mediators. Because miR-146a, a TLR4 microRNA (miRNA), can regulate TLR4 signaling during inflammatory responses, this study investigated the effects of aerobic exercise on TLR4-targeted miRNAs in AS. Apolipoprotein E-null mice fed a high-fat diet for 12 weeks were separated into 3 groups: (i) no treatment (AS), (ii) statin treatment (AD), or (iii) aerobic exercise (AE). Plaques and foam cells were observed in the untreated control and statin groups, respectively, but not in the AE group. Reduced angiotensin II (Ang II) and endothelin 1 (ET1) levels were observed in the AE group. Both treatment groups significantly altered the expression of inflammatory cytokine expression and reduced vascular TLR4 levels. Increased miR-146a and miR-126 and reduced miR-155 levels were observed in both treatment groups (all, P<0.001). miR-146a interacted with the 3' untranslated region of the TRAF6 gene, reducing its expression. Thus, aerobic exercise and statins may induce miR-146a expression, thereby reducing vascular TRAF and TLR4 signaling and vascular inflammatory injury in AS. Further analysis of this pathway may provide insight into the protective effects of aerobic exercise on vascular disease as well as new therapeutic targets.

Topics: Angiotensin II; Animals; Atherosclerosis; Disease Models, Animal; Endothelin-1; Epidermal Growth Factor; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Mice; MicroRNAs; NF-kappa B; Physical Conditioning, Animal; Signal Transduction; TNF Receptor-Associated Factor 6; Toll-Like Receptor 4

Atorvastatin, a hydroxymethylglutaryl-CoA reductase inhibitor, and endothelin-1 (ET-1) receptor antagonist have been separately indicated to ameliorate disease progression in atherosclerosis. However, no study has evaluated the effect of their combination on atherosclerosis. The objective of the current study was to evaluate the direct in vivo effects of a combination regimen of atorvastatin and ET-1 receptor antagonist on male New Zealand white rabbit models of atherosclerosis (injury-induced). Thirty-two atherosclerotic rabbits were divided into four experimental groups: (a) injury group - fed high-fat diet; (b) ET-1 receptor antagonist preventive group - fed high-fat diet, but with intragastric administration of the ET-1 receptor antagonist, darusentan; (c) combined preventive group - fed high-fat diet, but with intragastric administration of both darusentan and atorvastatin; and (d) treatment group - fed high-fat diet for the first 8 weeks, followed by normal diet and intragastric administration of both darusentan and atorvastatin up to 16 weeks. A further eight non-atherosclerotic rabbits were fed normal diet and classified as the control group. At the end of 8 and 16 weeks, compared with the injury group, the combined preventive group had significant reduction in both the concentration of serum lipids and inflammatory factors and atherosclerosis formation, indicative of a multifaceted anti-atherosclerotic impact. The relative area of atherosclerotic lesions in the injury group (30.84%) was significantly higher than the control group (4.62%; p < 0.05). The combined preventive group showed a significantly robust effect on lowering serum lipid, inflammatory cytokines, and maintained homeostatic balance of free radicals, and important downstream effectors like ET-1 and matrixmetalloproteinase-9. Our data show that atorvastatin and ET-1 receptor antagonist co-administration may decrease lipid levels, stabilize plaques and relieve vascular inflammation. By reducing the plaque burden, this regimen may minimize the risk of atherosclerotic plaque rupture or arterial occlusion.

Topics: Animals; Aorta, Abdominal; Atherosclerosis; Atorvastatin; Diet, High-Fat; Disease Models, Animal; Disease Progression; Down-Regulation; Drug Synergism; Drug Therapy, Combination; Endothelin A Receptor Antagonists; Endothelin-1; Heptanoic Acids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Iliac Artery; Inflammation Mediators; Lipids; Male; Matrix Metalloproteinase 9; NF-kappa B; Phenylpropionates; Plaque, Atherosclerotic; Pyrimidines; Pyrroles; Rabbits; RNA, Messenger

The effects of simulated heat waves on body weight, body temperature, and biomarkers of cardiac function in ApoE-/- mice were investigated. Heat waves were simulated in a meteorological environment simulation chamber according to data from a heat wave that occurred in July 2001 in Nanjing, China. Eighteen ApoE-/- mice were divided into control group, heat wave group, and heat wave BH4 group. Mice in the heat wave and BH4 groups were exposed to simulated heat waves in the simulation chamber. Mice in BH4 group were treated with gastric lavage with BH4 2 h prior to heat wave exposure. Results showed that the heat waves did not significantly affect body weight or ET-1 levels. However, mice in the heat wave group had significantly higher rectal temperature and NO level and lower SOD activity compared with mice in the control group (p < 0.01), indicating that heat wave had negative effects on cardiac function in ApoE-/- mice. Gastric lavage with BH4 prior to heat wave exposure significantly reduced heat wave-induced increases in rectal temperature and decreases in SOD activity. Additionally, pretreatment with BH4 further increased NO level in plasma. Collectively, these beneficial effects demonstrate that BH4 may potentially mitigate the risk of coronary heart disease in mice under heat wave exposure. These results may be useful when studying the effects of heat waves on humans.

Topics: Animals; Atherosclerosis; Biomarkers; Biopterins; Body Temperature; Body Weight; Coronary Disease; Drug Evaluation, Preclinical; Endothelin-1; Extreme Heat; Infrared Rays; Male; Mice; Mice, Knockout; Nitric Oxide; Random Allocation; Superoxide Dismutase

Our aim was to determine whether alterations in biomechanical properties of human diseased compared to normal coronary artery contribute to changes in artery responsiveness to endothelin-1 in atherosclerosis.. Concentration-response curves were constructed to endothelin-1 in normal and diseased coronary artery. The passive mechanical properties of arteries were determined using tensile ring tests from which finite element models of passive mechanical properties of both groups were created. Finite element modelling of artery endothelin-1 responses was then performed.. Maximum responses to endothelin-1 were significantly attenuated in diseased (27±3 mN, n=55) compared to normal (38±2 mN, n=68) artery, although this remained over 70% of control. There was no difference in potency (pD2 control=8.03±0.06; pD2 diseased=7.98±0.06). Finite element modelling of tensile ring tests resulted in hyperelastic shear modulus μ=2004±410 Pa and hardening exponent α=22.8±2.2 for normal wall and μ=2464±1075 Pa and α=38.3±6.7 for plaque tissue and distensibility of diseased vessels was decreased. Finite element modelling of active properties of both groups resulted in higher muscle contractile strain (represented by thermal reactivity) of the atherosclerotic artery model than the normal artery model. The models suggest that a change in muscle response to endothelin-1 occurs in atherosclerotic artery to increase its distensibility towards that seen in normal artery.. Our data suggest that an adaptation occurs in medial smooth muscle of atherosclerotic coronary artery to maintain distensibility of the vessel wall in the presence of endothelin-1. This may contribute to the vasospastic effect of locally increased endothelin-1 production that is reported in this condition.

Topics: Atherosclerosis; Biomechanical Phenomena; Coronary Vessels; Endothelin-1; Finite Element Analysis; Humans; In Vitro Techniques; Models, Cardiovascular; Myocardial Contraction

To study the relationship between non-alcoholic steatohepatitis (NASH) and atherosclerosis in young and middle-aged patients, and to provide clinical evidence that will aid in prevention and prediction of development of atherosclerosis or cardiovascular diseases in patients with non-alcoholic fatty liver disease (NAFLD).. Fifty-one patients with biopsy-proven NAFLD (18 to 60 years in age) were divided into two groups: cases with simple non-alcoholic fatty liver (NAFL, n = 11) and cases with NASH (n = 40). All subjects underwent physical examination and anthropometric measurements. Fasting serum was assayed by blood biochemistry. Insulin resistance was estimated by the homeostatic model assessment index (HOMA-IR). Serum levels of high-sensitivity C-reactive protein (hs-CRP), soluble intercellular adhesion molecule-1 (sICAM-1), and endothelin-1 (ET-1) were detected by enzyme-linked immunosorbent assay. Carotid intima-media thickness (CIMT) was estimated by carotid ultrasound. Brachial-ankle pulse wave velocity (baPWV) and ankle-brachial index were estimated using a volume-plethysmographic apparatus. Data for the two groups were summarized as mean +/- SD or interquartile range and intergroup differences were evaluated by paired t-test or Wilcoxon test, with two-sided P-values less than 0.05 indicating significance.. The serum levels of hs-CRP, sICAM-1, and ET-1 were significantly higher in the NASH group than the NAFL group (all P less than 0.001). In addition, the CIMT and baPWV were significantly higher in the NASH group than the NAFL group (both P less than 0.05). The HOMA-IR was also significantly higher in the NASH group than the NAFL group (P less than 0.001).. Liver inflammation and insulin resistance may play important, and possibly collaborative, roles in promoting arterial endothelial dysfunction and atherosclerosis in NAFLD patients. NASH patients, especially those who are young and middle-aged, may benefit from early monitoring and prevention strategies to help decrease the risk of developing severe cardiovascular diseases.

Topics: Adolescent; Adult; Atherosclerosis; C-Reactive Protein; Carotid Arteries; Carotid Intima-Media Thickness; Endothelin-1; Female; Humans; Insulin; Insulin Resistance; Intercellular Adhesion Molecule-1; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Young Adult

The article describes known atherosclerosis predictors of endothelial origin, which are diagnostic criteria for identifying's early stages of atherosclerosis, and can prevent the development of this disease and are used to monitor the effectiveness of the therapy The authors analyzed the possibility of using heparin as an early marker of atherosclerosis, based on the fact that the inhibition of lipoprotein lipase activity due hyperheparinemia resulting from depletion of mast cells due to endothelial dysfunction, leads to the disorders of lipid transporting system in the form of the resistant hyperlipidemia with the phenomena of dyslipidemia.

Topics: Atherosclerosis; Biological Transport; Biomarkers; Cell Count; Chemokine CCL2; Endothelial Cells; Endothelin-1; Heparin; Humans; Interleukin-1beta; Interleukin-6; Lipid Metabolism; Lipoprotein Lipase; Mast Cells; Nitric Oxide; Tumor Necrosis Factor-alpha

In the article the concentration of endothelin-1 in patients with different variants of APS was analyzed and its relationship with disease course, dyslipidemia, levels of antiphospholipid antibodies and ath rosclerotic vascular lesions was assessed. It was established that high levels of endothelin-1 is a circulating marker of early atherosclerosis, since !it was closely associated'with subclinical manifestations of atherosclerotic vascular lesions, lipid profile. The concentration of endothelin-1 significantly increased with active inflammation and with high levels of antiphospholipid antibodies and does not depend on age, sex, smoking, obesity and physical inactivity.

Topics: Adult; Antibodies, Antiphospholipid; Antiphospholipid Syndrome; Atherosclerosis; Biomarkers; Case-Control Studies; Disease Progression; Dyslipidemias; Early Diagnosis; Endothelial Cells; Endothelin-1; Endothelium, Vascular; Female; Humans; Inflammation; Lipid Metabolism; Male; Middle Aged; Motor Activity; Obesity; Smoking

To investigate the effect of plasminogen activator inhibitor-1 (PAI-1), tissue type plasminogen activator (t-PA), and endothelin-1 (ET-1) on the atherosclerosis progress in the maintenance hemodialysis patients.. We enrolled 19 patients with maintenance hemodialysis (MHD) and 11 healthy people as control. Patients were divided into 2 groups according to their age above or below 40 years old (11 and 8 in each, respectively), whereas the subjects in control group were below 40 years old. All the clinical information of the research subjects was collected: including age, gender, time of hemodialysis, blood pressure, blood urea nitrogen (BUN), and serum creatinine (SCr). Immunohistochemistry and pathological image analysis were used to investigate the pathological changes, calcification and the expression of PAI-1, t-PA, and ET-1 on the blood vessel.. Compared with the age-matched healthy control group, there were higher blood vascular media thickness, blood vascular media thickness/diagmeter ratio, blood vascular media thickness area/vascular inter-wall area ratio (P<0.05) and more calcification (P<0.05) in the the internal iliac artery in the chronic renal failure MHD patients. All the results were similar when compared the above 40 years old group with the below 40 years old one in the chronic renal failure MHD patients. There were positive correlation of blood vascular media thickness with age and blood pressure (P<0.05). Expression of PAI-1, ET-1, t-PA on the internal iliac artery vessel was elevated in the chronic renal failure MHD patients compared with the health control (P<0.05). The level of PAI-1 or ET-1 was much higher in the above 40 years old group than the below 40 years old one in the chronic renal failure MHD patients, whereas there was no significant difference in the t-PA expression between the 2 groups (P<0.05). There were positive correlation of PAI-1 or ET-1 expression with age and blood pressure (P<0.05). There were positive correlation of PAI-1 or ET-1 expression with blood vascular media thickness and calcification (P<0.05 or P<0.01). There was no correlation of hemodialysis time with blood vascular media thickness, calcification, PAI-1, t-PA, or ET-1 expressions.. MHD patients accompany with atherosclerosis which is severer in the patients above 40 years old than the patients below 40 years old. The higher of the blood pressure, the severer of the atherosclerosis. Abnormal expression of PAI-1 plays an important role in the progress of the atherosclerosis in the chronic renal failure MHD patients, whereas t-PA has no function in this process. The level of PAI-1 and ET-1 would be helpful to evaluating the degree of atherosclerosis in the chronic renal failure MHD patients. Hemodialysis time may not be a potential accelerator for atherosclerosis progression.

Topics: Adult; Atherosclerosis; Endothelin-1; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Plasminogen Activator Inhibitor 1; Renal Dialysis

Exposure to ambient air particulate matter (particles less than 10μm or PM10) has been shown to be an independent risk factor for the development and progression of atherosclerosis. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have well-established anti-inflammatory properties. The aim of this study was to determine the impact of statins on the adverse functional and morphological changes in blood vessels induced by PM10. New Zealand White rabbits fed with a high fat diet were subjected to balloon injury to their abdominal aorta followed by PM10/saline exposure for 4weeks±lovastatin (5mg/kg/day) treatment. PM10 exposure accelerated balloon catheter induced plaque formation and increased intimal macrophages and lipid accumulation while lovastatin attenuated these changes and promoted smooth muscle cell recruitment into plaques. PM10 impaired vascular acetylcholine (Ach) responses and increased vasoconstriction induced by phenylephrine as assessed by wire myograph. Supplementation of nitric oxide improved the impaired Ach responses. PM10 increased the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in blood vessels and increased the plasma levels of endothelin-1 (ET-1). Incubation with specific inhibitors for iNOS, COX-2 or ET-1 in the myograph chambers significantly improved the impaired vascular function. Lovastatin decreased the expression of these mediators in atherosclerotic lesions and improved endothelial dysfunction. However, lovastatin was unable to reduce blood lipid levels to the baseline level in rabbits exposed to PM10. Taken together, statins protect against PM10-induced cardiovascular disease by reducing atherosclerosis and improving endothelial function via their anti-inflammatory properties.

Topics: Animals; Atherosclerosis; Blood Vessels; Cholesterol, Dietary; Cyclooxygenase 2; Cytokines; Endothelin-1; Endothelins; Endothelium, Vascular; Environmental Exposure; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunohistochemistry; Lipids; Lovastatin; Male; Nitric Oxide Synthase Type II; Particulate Matter; Plaque, Atherosclerotic; Rabbits; Reactive Oxygen Species; Urban Health; Vascular Diseases

Loss of insulin action in the endothelium can cause endothelial dysfunction and atherosclerosis. Hyperglycemia and elevated fatty acids induced by diabetes mellitus can activate protein kinase C-β isoforms and selectively inhibit insulin signaling via phosphatidylinositol 3-kinase/Akt pathway to inhibit the activation of endothelial nitric oxide synthase and metabolic actions.. To demonstrate that overexpressing protein kinase C-β2 isoform in endothelial cells can cause selective insulin resistance and exacerbate atherosclerosis in the aorta.. Protein kinase C-β2 isoform was overexpressed in endothelial cells using a promoter of vascular endothelial cell cadherin. These mice were cross-bred with apoE-/- mice [Tg (Prkcb)apoE-/-]. On a Western diet, Tg(Prkcb)apoE-/- and apoE-/- mice did not differ in systemic insulin sensitivity, glucose tolerance, plasma lipid, or blood pressure. Insulin action in endothelial cells and femoral artery from Tg(Prkcb)apoE-/- mice was impaired by ≈40% with respect to Akt/endothelial nitric oxide synthase activation, and leukocyte-endothelial cell binding increased in cultured lung endothelial cells from Tg(Prkcb)apoE-/- mice compared with that from apoE-/- mice. Basal and angiotensin-stimulated big endothelin-1 levels were elevated in Tg(Prkcb)apoE-/- mice compared with apoE-/- mice. The severity of atherosclerosis in the aorta from Tg(Prkcb)apoE-/- mice increased by ≈70% as measured by en face fat staining and plaque content of the number of smooth muscle cells, macrophages, and extracellular matrix.. Specific protein kinase C-β2 activation in the endothelial cells caused dysfunction and accelerated atherosclerosis because of loss of insulin-stimulated Akt/endothelial nitric oxide synthase activation and angiotensin-induced increases in endothelin-1 expression.

Topics: Animals; Aorta; Apolipoproteins E; Atherosclerosis; Disease Models, Animal; Endothelin-1; Endothelium, Vascular; Female; Insulin Resistance; Isoenzymes; Male; Mice; Mice, Knockout; Nitric Oxide Synthase Type III; Protein Kinase C beta; Proto-Oncogene Proteins c-akt; Up-Regulation; Vascular Cell Adhesion Molecule-1

Minimally modified low-density lipoprotein (mmLDL) is a risk factor for cardiovascular disease. The present study investigated the effects of mmLDL on the expression of endothelin type A (ET(A)) receptors in coronary arteries. Rat coronary arteries were organ-cultured for 24 h. The contractile responses were recorded using a myographic system. ET(A) receptor mRNA and protein expressions were determined using real-time PCR and western blotting, respectively. The results showed that organ-culturing in the presence of mmLDL enhanced the arterial contractility mediated by the ET(A) receptor in a concentration-dependent and time-dependent manner. Culturing with mmLDL (10  μ g/mL) for 24 h shifted the concentration-contractile curves toward the left significantly with increased E(max) of 228% ± 20% from control of 100% ± 10% and significantly increased ET(A) receptor mRNA and protein levels. Inhibition of the protein kinase C, extracellular signal-related kinases 1 and 2 (ERK1/2), or NF- κ B activities significantly attenuated the effects of mmLDL. The c-Jun N-terminal kinase inhibitor or the p38 pathway inhibitor, however, had no such effects. The results indicate that mmLDL upregulates the ETA receptors in rat coronary arterial smooth muscle cells mainly via activating protein kinase C, ERK1/2, and the downstream transcriptional factor, NF- κ B.

Topics: Animals; Atherosclerosis; Coronary Vessels; Endothelin-1; Extracellular Signal-Regulated MAP Kinases; Inflammation; Lipoproteins, LDL; Myocytes, Smooth Muscle; NF-kappa B; Organ Culture Techniques; p38 Mitogen-Activated Protein Kinases; Protein Kinase C; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Receptor, Endothelin A; Signal Transduction; Up-Regulation

Endothelin (ET)-1 plays a role in vascular reactive oxygen species production and inflammation. ET-1 has been implicated in human atherosclerosis and abdominal aortic aneurysm (AAA) development. ET-1 overexpression exacerbates high-fat diet-induced atherosclerosis in apolipoprotein E(-/-) (Apoe(-/-)) mice. ET-1-induced reactive oxygen species and inflammation may contribute to atherosclerosis progression and AAA development.. Eight-week-old male wild-type mice, transgenic mice overexpressing ET-1 selectively in endothelium (eET-1), Apoe(-/-) mice, and eET-1/Apoe(-/-) mice were fed high-fat diet for 8 weeks. eET-1/Apoe(-/-) had a 45% reduction in plasma high-density lipoprotein (P<0.05) and presented ≥ 2-fold more aortic atherosclerotic lesions compared with Apoe(-/-) (P<0.01). AAAs were detected only in eET-1/Apoe(-/-) (8/21; P<0.05). Reactive oxygen species production was increased ≥ 2-fold in perivascular fat, media, or atherosclerotic lesions in the ascending aorta and AAAs of eET-1/Apoe(-/-) compared with Apoe(-/-) (P<0.05). Monocyte/macrophage infiltration was enhanced ≥ 2.5-fold in perivascular fat of ascending aorta and AAAs in eET-1/Apoe(-/-) compared with Apoe(-/-) (P<0.05). CD4(+) T cells were detected almost exclusively in perivascular fat (3/6) and atherosclerotic lesions (5/6) in ascending aorta of eET-1/Apoe(-/-) (P<0.05). The percentage of spleen proinflammatory Ly-6C(hi) monocytes was enhanced 26% by ET-1 overexpression in Apoe(-/-) (P<0.05), and matrix metalloproteinase-2 was increased 2-fold in plaques of eET-1/Apoe(-/-) (P<0.05) compared with Apoe(-/-).. ET-1 plays a role in progression of atherosclerosis and AAA formation by decreasing high-density lipoprotein, and increasing oxidative stress, inflammatory cell infiltration, and matrix metalloproteinase-2 in perivascular fat, vascular wall, and atherosclerotic lesions.

Topics: Adipose Tissue; Animals; Antigens, Ly; Aorta; Aortic Aneurysm, Abdominal; Apolipoproteins E; Atherosclerosis; Diet, High-Fat; Disease Models, Animal; Endothelin-1; Humans; Lipoproteins, HDL; Macrophages; Male; Matrix Metalloproteinase 2; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Monocytes; Plaque, Atherosclerotic; Reactive Oxygen Species; Up-Regulation

In human atherosclerosis, which is associated with elevated plasma and coronary endothelin (ET)-1 levels, ETA receptor antagonists improve coronary endothelial function. Mice overexpressing ET-1 specifically in the endothelium (eET-1) crossed with atherosclerosis-prone apolipoprotein E knockout mice (Apoe(-/-)) exhibit exaggerated high-fat diet (HFD)-induced atherosclerosis. Since endothelial dysfunction often precedes atherosclerosis development, we hypothesized that mice overexpressing endothelial ET-1 on a genetic background deficient in apolipoprotein E (eET-1/Apoe(-/-)) would have severe endothelial dysfunction. To test this hypothesis, we investigated endothelium-dependent relaxation (EDR) to acetylcholine in eET-1/Apoe(-/-) mice. EDR in mesenteric resistance arteries from 8- and 16-week-old mice fed a normal diet or HFD was improved in eET-1/Apoe(-/-) compared with Apoe(-/-) mice. Nitric oxide synthase (NOS) inhibition abolished EDR in Apoe(-/-). EDR in eET-1/Apoe(-/-) mice was resistant to NOS inhibition irrespective of age or diet. Inhibition of cyclooxygenase, the cytochrome P450 pathway, and endothelium-dependent hyperpolarization (EDH) resulted in little or no inhibition of EDR in eET-1/Apoe(-/-) compared with wild-type (WT) mice. In eET-1/Apoe(-/-) mice, blocking of EDH or soluble guanylate cyclase (sGC), in addition to NOS inhibition, decreased EDR by 36 and 30%, respectively. The activation of 4-aminopyridine-sensitive voltage-dependent potassium channels (Kv) during EDR was increased in eET-1/Apoe(-/-) compared with WT mice. We conclude that increasing eET-1 in mice that develop atherosclerosis results in decreased mutual dependence of endothelial signaling pathways responsible for EDR, and that NOS-independent activation of sGC and increased activation of Kv are responsible for enhanced EDR in this model of atherosclerosis associated with elevated endothelial and circulating ET-1.

Topics: Animals; Atherosclerosis; Endothelin-1; Endothelium, Vascular; Gene Expression Regulation; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Organ Culture Techniques; Severity of Illness Index; Vasodilation

Topics: Animals; Atherosclerosis; Endothelin-1; Endothelium, Vascular; Female; Insulin Resistance; Male; Protein Kinase C beta; Up-Regulation

The inflammation process in large vessels involves the up-regulation of vascular adhesion molecules such as endothelial cell selectin (E-selectin), intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) which are also known as the markers of atherosclerosis. We have reported that Chlorella 11-peptide exhibited effective anti-inflammatory effects. This peptide with an amino sequence Val-Glu-Cys-Tyr-Gly-Pro-Asn-Arg-Pro-Gln-Phe was further examined for its potential in preventing atherosclerosis in this study. In particular, the roles of Chlorella 11-peptide in lowering the production of vascular adhesion molecules, monocyte chemoattractant protein (MCP-1) and expression of endothelin-1 (ET-1) from endothelia (SVEC4-10 cells) were studied. The production of E-selectin, ICAM-1, VCAM-1 and MCP-1 in SVEC4-10 cells was measured with ELISA. The mRNA expression of ET-1 was analyzed by RT-PCR and agarose gel. Results showed that Chlorella 11-peptide significantly suppressed the levels of E-selectin, ICAM, VCAM, MCP-1 as well as ET-1 gene expression. The inhibition of ICAM-1 and VCAM-1 production by Chlorella 11-peptide was reversed in the presence of protein kinase A inhibitor (H89) which suggests that the cAMP pathway was involved in the inhibitory cause of the peptide. In addition, this peptide was shown to reduce the extent of increased intercellular permeability induced by combination of 50% of lipopolysaccharide (LPS)-activated RAW 264.7 cells medium and 50% normal SEVC cell culture medium (referred to as 50% RAW-conditioned medium). These data demonstrate that Chlorella 11-peptide is a promising biomolecule in preventing chronic inflammatory-related vascular diseases.

Topics: Animals; Atherosclerosis; Cell Adhesion Molecules; Cell Line; Chemokine CCL2; Chlorella; E-Selectin; Endothelin-1; Endothelium; Intercellular Adhesion Molecule-1; Macrophages; Mice; Peptides; Permeability; Vascular Cell Adhesion Molecule-1

Clinical and epidemiological evidence suggests that HIV infection and cocaine use are associated with an increased risk of premature atherosclerosis. The underlying mechanisms linking HIV infection and cocaine use with early atherosclerosis remain elusive.. Endothelin-1 (ET-1) levels in 360 African American participants in Baltimore, Maryland were measured. Quantile regression analysis was performed to examine the associations between ET-1, HIV infection, cocaine use, and other relevant clinical factors. The median of ET-1 in plasma, (1.05 pg/mL with interquartile range: 0.73, 1.40) for those with HIV infection was significantly higher than values for those without HIV infection (0.74 pg/mL with interquartile range: 0.61, 0.93). The median of ET-1 was markedly higher in chronic cocaine users (0.96 pg/mL with interquartile range: 0.71, 1.36) than that in non-cocaine users (0.72 pg/mL with interquartile range: 0.58, 1.06). Multivariate quantile regression suggested that HIV infection and duration of cocaine use were independently associated with plasma ET-1 levels after controlling for potential confounding factors.. This study may provide insight into the mechanism of premature atherosclerosis in HIV-infected cocaine users and suggest that measurement of ET-1 in plasma can be used as a marker of early atherosclerosis in HIV infected patients and cocaine users.

Topics: Adult; Atherosclerosis; Black or African American; Cocaine-Related Disorders; Endothelin-1; Endothelium, Vascular; Female; HIV Infections; Humans; Male; Middle Aged

Most clinical trials with vitamin E could not lower cholesterol and thus, have been deemed unsuccessful. Recently, tocotrienols, isomers of vitamin E have been found to lower LDL levels. To explore if tocotrienols could be the drug target for vitamin E, rabbits were kept on cholesterol diet for 60 days supplemented with tocotrienol-α, tocotrienol-δ, and tocotrienol-γ for the last 30 days. The serum cholesterol levels (in mmol/l) were 24.4 (tocotrienol-α), 34.9 (tocotrienol-δ), 19.8 (tocotrienol-γ) vs. 39.7 (control). Left ventricular function including aortic flow and developed pressure exhibited significantly improved recovery with tocotrienol-γ and -α, but not with tocotrienol-δ. The myocardial infarct size showed a similar pattern: 33% (tocotrienol-α), 23% (tocotrienol-γ), and 47% (tocotrienol-δ). To examine the molecular mechanisms of cardioprotective effects, gene expression profile was determined using Atlas 1.2/1.2II followed by determination of gene profiles using PedQuest 8.3 software. Based on genomic profiles, the following cholesterol-related proteins were examined: FABP, TGF-β (cholesterol suppresses TGF-β), ET-1 (increased by hypercholesterolemia), SPOT 14 (linked with hypercholesterolemia), and matrix metalloproteinase (MMP) 2 and MMP9 (cholesterol regulates MMP2 and MMP9 expression) in the heart. Consistent with the cardioprotective effects of tocotrienol-α and -γ, these two isomers reduced ET-1, decreased MMP2 and MM9, increased TGF-β and reduced SPOT 14, while tocotrienol-δ had no effects. The results of the present study demonstrate that the two isomers of tocotrienols, α and γ, render the hypercholesterolemic hearts resistant to ischemic reperfusion injury by lowering several hypercholesterolemic proteins including MMP2, MMP9, ET-1, and SPOT 14 and upregulating TGF-β.

Topics: Animals; Anticholesteremic Agents; Atherosclerosis; Cardiotonic Agents; Cholesterol; Chromans; Diet, High-Fat; Endothelin-1; Female; Gene Expression; Gene Expression Profiling; Heart; Hypercholesterolemia; In Vitro Techniques; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Myocardial Reperfusion Injury; Myocardium; Rabbits; Rats; Rats, Sprague-Dawley; Receptors, Estrogen; Sex Factors; Transforming Growth Factor beta; Vitamin E

The protective effects of estrogen replacement therapy (ERT) against oxidative injury and endothelial dysfunction in the aortic tissues induced with nicotine in ovariectomized (OVX) rats were investigated.. Female rats were divided into a sham-operated group (n = 8) and four groups in which OVX rats received either vehicle (0.1 ml sesame oil, i.m., n = 8), or nicotine (0.1 mg/kg, s.c., n = 8), or estradiol benzoate (0.1 mg/kg, i.m., n = 8), or both nicotine and estradiol benzoate (n = 8) starting at week 5 after the surgery and continuing for the following 6 weeks.. ERT was effective in preventing the rise in plasma lipid profile, atherogenic index and the level of induced endothelin-1 (ET-1) in nicotine-treated OVX rats. It also reduced aortic malondialdehyde, hydroxyproline levels, calcium content and caspase-3 expression induced in nicotine-treated OVX rats. ERT increased serum estradiol, high-density lipoprotein cholesterol and nitric oxide levels in nicotine-treated OVX rats. Furthermore, ERT was effective in restoring reduced glutathione and cyclic guanosine monophosphate contents and endothelial nitric oxide synthase expression in aortic tissues of nicotine-treated OVX rats.. Short-term ERT could be a promising therapeutic strategy to minimize nicotine-induced oxidative stress and vascular endothelial dysfunction in menopausal women subjected to environmental smoke.

Topics: Animals; Aorta, Thoracic; Atherosclerosis; Calcium; Endothelin-1; Endothelium, Vascular; Estradiol; Estrogen Replacement Therapy; Female; Humans; Hydroxyproline; Lipids; Malondialdehyde; Models, Animal; Nicotine; Nitric Oxide; Nitric Oxide Synthase Type III; Ovariectomy; Oxidative Stress; Rats; Rats, Wistar

The heme oxygenase-1 (HO-1) / carbon monoxide (CO) system has been presumed as a therapeutic target for preventing atherosclerosis. However, the exact mechanism(s) underlying this system remains largely undefined. This study aims to examine the influence of induction/inhibition of HO-1 on atherosclerotic plaque using pharmacological approaches and to elucidate potential mechanisms. Rabbits were randomly assigned to receive a standard diet (control group), high fat diet (HFD), HFD plus HO inducer hemin (HFD + H group), and HFD plus an HO inhibitor, zinc protoporphyrin-9 (ZnPP9, HFD + Z group). Atherosclerotic plaque was evaluated using oil red O staining and histological analyses. Immunohistochemistry, western blotting, and RT-PCR were employed to study the expression of HO-1 and endothelin-1 (ET-1). Levels of CO, nitric oxide (NO), eNOS/iNOS activities, NF-κB activity, and TNF-α level were determined. No significant differences of serum lipid levels were observed among the HFD, HFD + Z, and HFD + H groups. In rabbits, HFD induced typical atherosclerotic plaque and increased intima/media thickness ratio, which was markedly reduced in the HFD + H group and further aggravated in the HFD + Z group. Furthermore, hemin increased HO-1 expression, CO levels, and eNOS activity, while decreasing iNOS levels, ET-1 expression, NF-κB activity, and TNF-α level. ZnPP9 caused opposite effects. Induction of the endogenous HO-1/CO system by hemin can prevent atherosclerosis though increasing CO levels, regulating eNOS activity, NF-κB activity, TNF-α levels, and ET-1 levels in rabbits. Our results add new evidence for the importance of HO-1 in the genesis and development of atherosclerosis and provide several possible mechanisms underlying the anti-atherosclerosis effects of HO-1.

Topics: Animals; Aorta; Atherosclerosis; Carbon Monoxide; Diet, High-Fat; Endothelin-1; Heme Oxygenase-1; Hemin; Lipid Metabolism; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Protoporphyrins; Rabbits; RNA, Messenger; Tumor Necrosis Factor-alpha

Endothelin-1 (ET-1) promotes atherosclerosis. We tested whether spleen tyrosine kinase (Syk) mediates tumor necrosis factor-α (TNF-α)-induced ET-1 upregulation in human aortic endothelial cells (HAECs) and sought to identify the signal pathways involved. TNF-α-induced reactive oxygen species (ROS) activated Syk and phosphatidylinositol 3-kinase (PI3K), which was required for the activation of AP-1 and subsequent ET-1 gene transcription. ROS mediated c-Jun NH(2)-terminal kinase (JNK) is also required for AP-1 activation, but Syk and PI3K regulated AP-1 activation independently of JNK. Through regulation of ET-1 production, Syk could be implicated in atherosclerosis.

Topics: Aorta; Atherosclerosis; Cells, Cultured; Endothelial Cells; Endothelin-1; Enzyme Activation; Enzyme Inhibitors; Humans; Intracellular Signaling Peptides and Proteins; JNK Mitogen-Activated Protein Kinases; Phosphatidylinositol 3-Kinases; Protein-Tyrosine Kinases; Reactive Oxygen Species; RNA, Small Interfering; Syk Kinase; Transcription Factor AP-1; Tumor Necrosis Factor-alpha; Up-Regulation

It has been commonly accepted that second-hand smoke (SHS) is associated with atherosclerosis and endothelial dysfunction. There is growing evidence that the changes might begin in childhood. Unfortunately, no study has focused on the early atherosclerosis of Tibetan adolescents exposed to SHS.. We aimed to investigate the endothelial function and carotid atherosclerosis in healthy school-aged Tibetan male adolescents.. All passive smoking participants (SHS) were students were 16 years old and male, and were recruited through middle schools in Lhasa city. In total 624 subjects were accepted after excluding subjects who actively smoked. The adolescents were divided into three groups according to serum cotinine level: high cotinine group (High Group) with 205 boys, intermediate cotinine group (Intermediate Group) with 210 boys, and low cotinine group (Low Group) with 209 boys. Venous blood was sampled for the measurement of cotinine concentration, lipid profile and endothelin-1 (ET-1) quantitation. High-resolution B-mode ultrasonography was performed to evaluate carotid intima-media thickness (cIMT) and intima smoothness. The invasive vascular endothelial function was evaluated through the measurement of flow-mediated dilation (FMD) with B-mode ultrasound and ankle-brachial index (ABI) by using a blood pressure cuff and a Doppler instrument.. No statistical significance was found between groups in total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglyceride, ApoA-I, systolic blood pressure, diastolic blood pressure, and heart rate (p>0.05). In the lipid profile, only apolipoprotein B (ApoB) values were different between groups: ApoB in the High Group was higher than in the Low Group (p=0.0164). Plasma ET-1 concentrations in the High Group were also much higher than in the Intermediate and Low Groups (p=0.0112, p<0.001). The cIMT and intima smoothness had deteriorated in the High Group compared with the Low Group (p<0.001 and p<0.05 respectively). FMD and ABI, which indicate vascular endothelial function, was decreased in the High Group compared with the Intermediate and Low Groups (FMD, p<0.001; ABI, p<0.001).. SHS was associated with sub-clinical carotid atherosclerosis and endothelial dysfunction in Tibetan school-aged male adolescents. Considering the widespread exposure to SHS and the clinical relevance of early atherosclerosis, this result is of public health importance in Tibet, where health education is not satisfactory. Data from our study emphasize the importance of endorsing smoke-free environments for adolescents.

Topics: Adolescent; Ankle Brachial Index; Atherosclerosis; Carotid Artery, Common; Carotid Intima-Media Thickness; Endothelin-1; Endothelium, Vascular; Femoral Artery; Hemorheology; Humans; Male; Multivariate Analysis; Regression Analysis; Risk Factors; Tibet; Tobacco Smoke Pollution; Vasodilation

Combustion emissions cause pro-atherosclerotic responses in apolipoprotein E-deficient (ApoE/⁻) mice, but the causal components of these complex mixtures are unresolved. In studies previously reported, ApoE⁻/⁻ mice were exposed by inhalation 6 h/day for 50 consecutive days to multiple dilutions of diesel or gasoline exhaust, wood smoke, or simulated "downwind" coal emissions. In this study, the analysis of the combined four-study database using the Multiple Additive Regression Trees (MART) data mining approach to determine putative causal exposure components regardless of combustion source is reported. Over 700 physical-chemical components were grouped into 45 predictor variables. Response variables measured in aorta included endothelin-1, vascular endothelin growth factor, three matrix metalloproteinases (3, 7, 9), metalloproteinase inhibitor 2, heme-oxygenase-1, and thiobarbituric acid reactive substances. Two or three predictors typically explained most of the variation in response among the experimental groups. Overall, sulfur dioxide, ammonia, nitrogen oxides, and carbon monoxide were most highly predictive of responses, although their rankings differed among the responses. Consistent with the earlier finding that filtration of particles had little effect on responses, particulate components ranked third to seventh in predictive importance for the eight response variables. MART proved useful for identifying putative causal components, although the small number of pollution mixtures (4) can provide only suggestive evidence of causality. The potential independent causal contributions of these gases to the vascular responses, as well as possible interactions among them and other components of complex pollutant mixtures, warrant further evaluation.

Topics: Administration, Inhalation; Air Pollutants; Ammonia; Animals; Aorta; Apolipoproteins E; Atherosclerosis; Carbon Monoxide; Coal; Endothelin-1; Heme Oxygenase-1; Male; Matrix Metalloproteinases; Mice; Mice, Knockout; Nitrogen Oxides; Smoke; Sulfur Dioxide; Thiobarbituric Acid Reactive Substances; Tissue Inhibitor of Metalloproteinase-2; Vascular Endothelial Growth Factor A; Vehicle Emissions; Wood

Diabetes mellitus is the leading cause of vascular complications such as atherosclerosis. This study was designed to investigate whether Prunella vulgaris (APV) would inhibit diabetic atherosclerosis in db/db mice with type 2 diabetes. The db/db mice were treated with high fat/high cholesterol (HFHC) diet and an aqueous extract of APV (100 and 200 mg/kg/day) for eight weeks to examine the long-term effect on metabolic abnormalities and diabetic atherosclerosis. APV treatment markedly lowered blood glucose and systolic blood pressure. The db/db mice experienced an increase in blood urea nitrogen as well as a decrease of creatinine clearance, the latter of which was restored by treatment with APV. Treatment with APV markedly decreased total plasma cholesterol, triglyceride, and LDL-cholesterol and also increased the HDL-cholesterol. In addition, malondialdehyde and TGF-β1 were decreased by treatment of APV. On the other hand, total NO level was decreased in db/db mice. However, the NO level was increased by treatment with APV, suggesting an association with vascular dysfunction. Vascular relaxation of aortic rings by acetylcholine or SNP-inducement was ameliorated by APV in a dose-dependent manner. Damage of vascular intima and hypertrophic of media were observed in db/db mice; however its dysfunction was improved by the treatment of APV. APV treatment significantly reduced the aortic expressions of ICAM-1, VCAM-1, ET-1, and nitrotyrosine. Furthermore, expression of eNOS in aortic was remarkably increased by APV treatment. Taken together, APV suppressed hyperglycemia and diabetic vascular dysfunction in HFHC diet-db/db mice. The present data suggest that Prunella vulgaris may prevent development of diabetic atherosclerosis.

Topics: Acetylcholine; Animals; Aorta; Atherosclerosis; Blood Glucose; Blood Pressure; Blood Urea Nitrogen; Cholesterol, Dietary; Creatinine; Diabetes Complications; Diabetes Mellitus, Type 2; Diet, High-Fat; Dose-Response Relationship, Drug; Endothelin-1; Hyperglycemia; Hypertrophy; Hypoglycemic Agents; Intercellular Adhesion Molecule-1; Lipids; Male; Malondialdehyde; Mice; Mice, Inbred Strains; Mice, Knockout; Nitric Oxide; Phytotherapy; Plant Extracts; Prunella; Transforming Growth Factor beta1; Tunica Intima; Tunica Media; Tyrosine; Vascular Cell Adhesion Molecule-1; Vasodilation

Endothelin (ET)-1 plays an important pathophysiological role in several vascular diseases including hypertension and atherosclerosis. Transgenic mice overexpressing human preproET-1 selectively in the endothelium (eET-1) exhibit vascular injury in the absence of blood pressure elevation. ET-1 overexpression may induce vascular injury by inducing changes in gene expression. To understand mechanisms whereby ET-1 induces vascular damage, vascular gene expression profiling was performed using DNA microarrays. RNA from mesenteric arteries of male and female young (6-7 wk) and mature (6-8 mo) eET-1 and wild-type (WT) mice was isolated, and changes in gene expression were determined by genome-wide expression profiling using Illumina microarray and FlexArray software. Data were analyzed using a relaxed and a stringent statistical approach. The gene lists were compared and analyzed as well with Ingenuity Pathway Analysis. The most common change was an increase in the expression of lipid metabolism genes. Four of these genes were validated by qPCR, cyp51, dgat2, and scd1 genes in young and elovl6 in both young and mature male mice, supporting a role of ET-1 in atherosclerosis. To test the hypothesis that ET-1 participates in mechanisms leading to atherosclerosis, we crossed eET-1 with atherosclerosis-prone apoE(-/-) mice to determine whether ET-1 overexpression exacerbates high-fat diet (HFD)-induced atherosclerosis using oil red O staining of descending thoracic aorta. HFD increased lipid plaques by 3-, 27-, and 86-fold in eET-1, apoE(-/-), and crossed mice, respectively, vs. WT. This suggests that increased endothelial ET-1 expression results in early changes in gene expression in the vascular wall that enhance lipid biosynthesis and accelerate progression of atherosclerosis.

Topics: Aging; Animals; Apolipoproteins E; Atherosclerosis; Blood Vessels; Cholesterol; Diet; Endothelin-1; Endothelium, Vascular; Female; Gene Expression Profiling; Gene Expression Regulation; Humans; Lipids; Male; Mice; Mice, Knockout; Oligonucleotide Array Sequence Analysis; Organ Specificity; Reproducibility of Results

To determine vascular signaling pathways involved in inhaled air pollution (vehicular engine emission) exposure-induced exacerbation of atherosclerosis that are associated with onset of clinical cardiovascular events.. To elucidate the role of oxidized low-density lipoprotein (oxLDL) and its primary receptor on endothelial cells, the lectin-like oxLDL receptor (LOX-1), in regulation of endothelin-1 expression and matrix metalloproteinase activity associated with inhalational exposure to vehicular engine emissions.. Atherosclerotic apolipoprotein E knockout mice were exposed by inhalation to filtered air or mixed whole engine emissions (250 μg particulate matter [PM]/m(3) diesel + 50 μg PM/m(3) gasoline exhausts) 6 h/d for 7 days. Concurrently, mice were treated with either mouse IgG or neutralizing antibodies to LOX-1 every other day. Vascular and plasma markers of oxidative stress and expression proatherogenic factors were assessed. In a parallel study, healthy human subjects were exposed to either 100 μg PM/m(3) diesel whole exhaust or high-efficiency particulate air and charcoal-filtered "clean" air (control subjects) for 2 hours, on separate occasions.. Mixed emissions exposure increased oxLDL and vascular reactive oxygen species, as well as LOX-1, matrix metalloproteinase-9, and endothelin-1 mRNA expression and also monocyte/macrophage infiltration, each of which was attenuated with LOX-1 antibody treatment. In a parallel study, diesel exhaust exposure in volunteer human subjects induced significant increases in plasma-soluble LOX-1.. These findings demonstrate that acute exposure to vehicular source pollutants results in up-regulation of vascular factors associated with progression of atherosclerosis, endothelin-1, and matrix metalloproteinase-9, mediated through oxLDL-LOX-1 receptor signaling, which may serve as a novel target for future therapy.

Topics: Adolescent; Adult; Air Pollutants; Animals; Antibodies, Neutralizing; Aorta; Apolipoproteins E; Atherosclerosis; Endothelin-1; Endothelium, Vascular; Humans; Lipid Peroxidation; Lipoproteins, LDL; Male; Matrix Metalloproteinase 9; Mice; Mice, Knockout; Oxidative Stress; Reactive Oxygen Species; Scavenger Receptors, Class E; Signal Transduction; Thiobarbituric Acid Reactive Substances; Up-Regulation; Vehicle Emissions; Young Adult

To examine biomarkers of oxidative stress (oxs), and endothelin (ET)-1, in hypertensive patients with atherosclerotic renal artery stenosis (ARAS) and to evaluate the effect of percutaneous transluminal renal angioplasty (PTRA).. Baseline measurements were made immediately before renal angiography in patients with suspected ARAS (significant ARAS, n = 83, and non-RAS, n = 59) and in 20 healthy, matched controls. In patients with ARAS, analyses were repeated 4 weeks after PTRA. All patients were treated with statins and acetylsalicylic acid throughout.. At baseline there were no significant differences between groups in biomarkers of oxs, whereas high-sensitivity C-reactive protein and blood leukocytes were significantly elevated in group ARAS versus both healthy controls and group non-RAS. Plasma levels of ET-1 and uric acid were significantly increased in group ARAS versus healthy controls prior to angiography and were significantly reduced compared to baseline 4 weeks after PTRA. PTRA had no significant effects on biomarkers of oxs, inflammation or serum creatinine concentrations.. ARAS patients on treatment with antihypertensive agents, acetylsalicylic acid and statins showed elevated inflammatory indices but no increase in oxs. PTRA had no significant effects on inflammatory indices 4 weeks after intervention but reduced plasma ET-1 and uric acid.

Topics: Aged; Angioplasty; Atherosclerosis; Biomarkers; Endothelin-1; Female; Humans; Hypertension; Male; Middle Aged; Oxidative Stress; Renal Artery Obstruction; Uric Acid

The increased incidence of cardiovascular disease in women with polycystic ovary syndrome (PCOS) has prompted researchers to look for indicators of early atherosclerotic changes in these patients. One of the earliest stages of atherogenesis is endothelial cell dysfunction. The aim of this study was to assess the levels of selected plasma markers of endothelial injury [E-selectin, endothelin-1 (ET-1) and von Willebrand Factor antigen (vWF:Ag)] in PCOS women before and after six months of treatment.. 32 patients with PCOS aged 18-36 years (mean age 25.16 ± 5.80) were included in the study. The control group consisted of 20 healthy women matched for age and body mass. The levels of ET-1, vWF:Ag, E-selectin, fasting glucose, insulin, total cholesterol, HDL and LDL-cholesterol and triglycerides were assessed. In the PCOS group, all these tests were repeated after six months of treatment.. The study showed higher levels of vWF:Ag (p = 0.043), E selectin (p = 0.028), insulin (p = 0.044), glucose (p = 0.036) and LDL (p = 0.006) in PCOS patients versus healthy women. A positive correlation was demonstrated between E selectin and glucose (p = 0.0001), triglycerides (p = 0.014) and uric acid (p = 0.008). vWF:Ag levels showed a positive correlation with glucose (p = 0.04) and triglycerides (p = 0.036). A positive correlation was also found between ET-1 and total cholesterol levels (p = 0.012) in PCOS women. After treatment, there was a significant reduction in E-selectin levels from baseline (p = 0.002) and an increase in the levels of HDL (p = 0.0002) and triglycerides (p = 0.033).. Elevated levels of vWF:Ag and E selectin in PCOS women suggest endothelial dysfunction in this group of patients. Glucose and triglyceride are significant factors affecting endothelial function in PCOS.

Topics: Adolescent; Adult; Atherosclerosis; Biomarkers; Case-Control Studies; E-Selectin; Endothelin-1; Endothelium, Vascular; Female; Humans; Polycystic Ovary Syndrome; von Willebrand Factor

Because both endothelin-1 (ET-1) and angiotensin II (AngII) are independent mediators of arterial remodeling, we sought to determine the role of ET receptor inhibition in AngII-accelerated atherosclerosis and aortic aneurysm formation. We administered saline or AngII and/or bosentan, an endothelin receptor antagonist (ERA) for 7, 14, or 28 days to 6-week- and 6-month-old apolipoprotein E-knockout mice. AngII treatment increased aortic atherosclerosis, which was reduced by ERA. ET-1 immunostaining was localized to macrophage-rich regions in aneurysmal vessels. ERA did not prevent AngII-induced aneurysm formation but instead may have increased aneurysm incidence. In AngII-treated animals with aneurysms, ERA had a profound effect on the non-aneurysmal thoracic aorta via increasing wall thickness, collagen/elastin ratio, wall stiffness, and viscous responses. These observations were confirmed in acute in vitro collagen sheet production models in which ERA inhibited AngII's dose-dependent effect on collagen type 1 α 1 (COL1A1) gene transcription. However, chronic treatment reduced matrix metalloproteinase 2 mRNA expression but enhanced COL3A1, tissue inhibitor of metalloproteinase 1 (TIMP-1), and TIMP-2 mRNA expressions. These data confirm a role for the ET system in AngII-accelerated atherosclerosis but suggest that ERA therapy is not protective against the formation of AngII-induced aneurysms and can paradoxically stimulate a chronic arterial matrix remodeling response.

Topics: Angiotensin II; Animals; Antihypertensive Agents; Aorta; Aortic Aneurysm; Apolipoproteins E; Atherosclerosis; Biomechanical Phenomena; Bosentan; Cardiovascular Agents; Cell Adhesion; Collagen; Down-Regulation; Endothelin-1; Integrin beta1; Interferon-gamma; Mice; Mice, Knockout; Stress, Physiological; Sulfonamides; Vasoconstrictor Agents

Recent epidemiological studies suggest that traffic-related air pollution may have detrimental effects on cardiovascular health. Previous studies reveal that gasoline emissions can induce several enzyme pathways involved in the formation and development of atherosclerotic plaques. As a direct comparison, the present study examined the impact of diesel engine emissions on these pathways, and further examined the effects on vascular lesion pathology. Apolipoprotein E-null mice were simultaneously placed on a high-fat chow diet and exposed to four concentrations, plus a high concentration exposure with particulates (PM) removed by filtration, of diesel emissions for 6 h/day for 50 days. Aortas were subsequently assayed for alterations in matrix metalloproteinase-9, endothelin-1, and several other biomarkers. Diesel induced dose-related alterations in gene markers of vascular remodeling and aortic lipid peroxidation; filtration of PM did not significantly alter these vascular responses, indicating that the gaseous portion of the exhaust was a principal driver. Immunohistochemical analysis of aortic leaflet sections revealed no net increase in lesion area, but a significant decrease in lipid-rich regions and increasing trends in macrophage accumulation and collagen content, suggesting that plaques were advanced to a more fragile, potentially more vulnerable state by diesel exhaust exposure. Combined with previous studies, these results indicate that whole emissions from mobile sources may have a significant role in promoting chronic vascular disease.

Topics: Air Pollutants; Animals; Aorta; Apolipoproteins E; Atherosclerosis; Collagen; Dietary Fats; Dose-Response Relationship, Drug; Endothelin-1; Immunohistochemistry; Inhalation Exposure; Lipid Peroxidation; Macrophages; Male; Matrix Metalloproteinase 9; Mice; Mice, Knockout; Vehicle Emissions

Our lab has shown that left circumflex coronary artery (LCX) perivascular adipose tissue (PAT) blunts endothelin-1 (ET-1)-induced maximal contractions in normal pigs on low- and high-fat diets. Other studies report that PAT exerts anticontractile effects on agonist-induced arterial contraction via release of a relaxing factor that acts on the underlying vasculature. The purpose of this study was to test the hypotheses that PAT blunts LCX contraction in familial hypercholesterolemic pigs and that exercise training (Ex) augments this anticontractile effect. Male familial hypercholesterolemic pigs were divided into Ex (n = 13) and sedentary (Sed) (n = 15) groups. LCX reactivity to angiotensin II (ANG II), bradykinin (BK), ET-1, and sodium nitroprusside (SNP) was evaluated in vitro with intact or removed PAT in Sed and Ex familial hypercholesterolemic pigs. LCX relaxation induced by BK and SNP was not altered by Ex or PAT removal. LCX contractions stimulated by ANG II and ET-1 were not significantly altered by Ex or PAT removal across doses; however, Ex did act to significantly reduce ET-1 maximal contractions in familial hypercholesterolemic pig LCX compared with Sed familial hypercholesterolemic pig LCX, independent of PAT (P < 0.05). We conclude that LCX PAT in Sed and Ex familial hypercholesterolemic pigs exerts no substantial anticontractile influence over LCX vasomotor responses to endogenous constrictors such as ANG II and ET-1. Our results suggest that exercise training significantly reduces familial hypercholesterolemic pig LCX maximal contractile responses to the endogenous constrictor ET-1, independent of PAT.

Topics: Adipose Tissue; Angiotensin II; Animals; Atherosclerosis; Bradykinin; Coronary Vessels; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin-1; Hyperlipoproteinemia Type II; Male; Nitroprusside; Physical Exertion; Sedentary Behavior; Swine; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

The combination of obesity and its associated risk factors, such as insulin resistance and inflammation, results in the development of atherosclerosis. However, the effects of periodontitis on atherosclerosis in an obese body remain unclear. The aim of the study was to investigate the effects of ligature-induced periodontitis in Zucker fatty rats on initiation of atherosclerosis by evaluating aortic insulin resistance. Zucker fatty rats (n=24) were divided into two groups. In the periodontitis group, periodontitis was ligature-induced for 4 weeks, whereas the control group was left unligated. After the 4-week experimental period, descending aorta was used for measuring the levels of lipid deposits, immunohistochemical analysis, and evaluation of gene expression. Levels of serum C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-alpha), and insulin were also measured. Rats in the periodontitis group had significantly enhanced lipid deposits in the aorta, but not in the control group. Expression of suppressor of cytokine signaling 3, vascular cell adhesion molecule 1, reactive oxygen species, nitrotyrosine, and endothelin-1 in the periodontitis group was more intense than that in the control group. Significantly decreased levels of phosphatidylinositol 3-kinase (Pi3k) catalytic beta-polypeptide (Pi3kcb), Pi3kp85, and insulin receptor substrate 1 and 2 were observed in the periodontitis group. Levels of serum CRP and TNF-alpha were significantly increased in the periodontitis group. Under insulin-stimulated conditions, aorta in the periodontitis group altered the Akt phosphorylation. Periodontitis in obesity induced the initial stage of atherosclerosis and disturbed aortic insulin signaling.

Topics: Animals; Aorta; Atherosclerosis; Endothelin-1; Gene Expression Profiling; Insulin Resistance; Ligation; Male; Obesity; Oligonucleotide Array Sequence Analysis; Periodontitis; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; Rats, Zucker; Vascular Cell Adhesion Molecule-1; Vascular Endothelial Growth Factor A

Animal and clinical studies have suggested that polyphenols in fruits, red wine, and tea may delay the development of atherosclerosis through their antioxidant and anti-inflammatory properties. We investigated whether individual dietary polyphenols representing different polyphenolic classes, namely quercetin (flavonol), (-)-epicatechin (flavan-3-ol), theaflavin (dimeric catechin), sesamin (lignan), or chlorogenic acid (phenolic acid), reduce atherosclerotic lesion formation in the apolipoprotein E (ApoE)(-/-) gene-knockout mouse.. Quercetin and theaflavin (64-mg/kg body mass daily) significantly attenuated atherosclerotic lesion size in the aortic sinus and thoracic aorta (P<0.05 versus ApoE(-/-) control mice). Quercetin significantly reduced aortic F(2)-isoprostane, vascular superoxide, vascular leukotriene B(4), and plasma-sP-selectin concentrations; and augmented vascular endothelial NO synthase activity, heme oxygenase-1 protein, and urinary nitrate excretion (P<0.05 versus control ApoE(-/-) mice). Theaflavin showed similar, although less extensive, significant effects. Although (-)-epicatechin significantly reduced F(2)-isoprostane, superoxide, and endothelin-1 production (P<0.05 versus control ApoE(-/-) mice), it had no significant effect on lesion size. Sesamin and chlorogenic acid treatments exerted no significant effects. Quercetin, but not (-)-epicatechin, significantly increased the expression of heme oxygenase-1 protein in lesions versus ApoE(-/-) controls.. Specific dietary polyphenols, in particular quercetin and theaflavin, may attenuate atherosclerosis in ApoE(-/-) gene-knockout mice by alleviating inflammation, improving NO bioavailability, and inducing heme oxygenase-1. These data suggest that the cardiovascular protection associated with diets rich in fruits, vegetables, and some beverages may in part be the result of flavonoids, such as quercetin.

Topics: Animals; Anti-Inflammatory Agents; Aorta; Aortic Diseases; Apolipoproteins E; Atherosclerosis; Biflavonoids; Biomarkers; Catechin; Chlorogenic Acid; Cholesterol; Diet; Dioxoles; Disease Models, Animal; Endothelin-1; Endothelium, Vascular; F2-Isoprostanes; Fatty Acids; Flavonoids; Heme Oxygenase-1; Inflammation; Leukotriene B4; Lignans; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitrates; Nitric Oxide; Nitric Oxide Synthase Type III; Nitrites; Oxidative Stress; P-Selectin; Phenols; Polyphenols; Quercetin; Superoxides

Nut consumption has beneficial effects on protection for development of atherosclerotic process.. Single intervention study design was used to determine the effects of hazelnut-enriched diet (1 g/kg/day) during 4 weeks period on atherogenic tendency of low-density lipoprotein (LDL) by evaluating susceptibility of LDL to oxidation, alpha-tocopherol content of LDL, LDL subfractions, plasma oxidized (ox) LDL, lipid and lipoprotein levels in normolipidemic healthy subjects (n=21). Statistical analysis was performed using paired t test, ANOVA for repeated measurements test, Pearson's and Spearman correlation analyses.. Lag time for oxidation (baseline 54.6+/- 12.3 min, 15th day 59.3+/- 13.4 min, 30th day 65.2+/- 17.8 min, p=0.001) and ,alpha--tocopherol content of LDL (baseline 4.82+/- 1.2 microg/mg LDL protein, 15th day 4.88+/- 1.4 microg/mg LDL protein, 30th day 5.35+/- 1.7 microg/mg LDL protein, p=0.02) were found to be increased while ox-LDL levels (baseline 57.2+/- 16.2 U/L, 15th day 51.2+/- 13.6 U/L, 30th day 48.2+/- 14.2 U/L, p=0.001) decreased during the study period. Total cholesterol, LDL-cholesterol, apolipoprotein (apo) B and apo B/apo AI ratio were found to be significantly lower while apo AI was higher (p<0.05). In respect to LDL subfraction, ratio of large/small LDL was significantly increased at the end of the study (baseline 3.79+/- 1.35, 15th day 3.41+/- 1.60, 30th day 4.28+/- 2.44, p= 0.046).. Hazelnut-enriched diet may play important role in decrease in atherogenic tendency of LDL by lowering the susceptibility of LDL to oxidation and plasma ox-LDL levels, and increasing the ratio of large/small LDL beyond its beneficial effect on lipid and lipoprotein levels.

Topics: Adult; alpha-Tocopherol; Apolipoproteins B; Atherosclerosis; Cholesterol; Cholesterol, LDL; Corylus; Endothelin-1; Energy Intake; Female; Humans; Lipids; Lipoproteins; Lipoproteins, LDL; Male; Plasminogen Activator Inhibitor 1; Reference Values; Triglycerides; Vascular Cell Adhesion Molecule-1; Young Adult

Angiotensin II plays an important role in the pathogenesis of atherosclerosis. This study was designed to examine the effect of valsartan, an angiotensin receptor blocker, on atherosclerotic lesions in pulmonary arteries of rabbits with atherosclerosis induced by a high-cholesterol (HC) diet.. Male New Zealand rabbits were randomly divided into four groups: control, HC without valsartan, HC with 3 mg/kg/d valsartan, and HC with 10 mg/kg/d valsartan. Following 12 weeks of treatment, serum lipid profiles were determined. Pulmonary arteries were harvested and stained with Sudan IV for evaluation of atherosclerotic lesions. The middle lobes of the rabbit lungs were isolated, embedded in paraffin, and sectioned and stained with haematoxylin and eosin. Nitric oxide (NO) and endothelin-1 (ET-1) levels were determined in pulmonary arteries by nitrate reductase assay and radioimmunoassay, respectively.. HC feeding altered serum lipid levels and induced atherosclerotic lesions in pulmonary arteries. Although 12 weeks of valsartan treatment failed to alter serum lipid levels, it significantly ameliorated HC-induced atherosclerotic lesions. Lesion areas, inflammatory cell infiltration, and occlusions of small arteries of lungs were reduced. Moreover, the endothelium-derived NO levels in pulmonary arteries were increased by valsartan treatment (10 mg/kg/d) compared to levels in the HC group. ET-1 levels were decreased by valsartan treatment compared to levels in the HC group. NO and ET-1 levels were not altered by valsartan at 3 mg/kg/d.. Our data demonstrates that HC diet-induced atherosclerotic lesions in rabbit pulmonary arteries can be ameliorated by treatment with valsartan, possibly through a NO and ET-1-dependent mechanism.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Atherosclerosis; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin-1; Endothelium, Vascular; Lipids; Male; Nitric Oxide; Pulmonary Artery; Rabbits; Tetrazoles; Treatment Outcome; Valine; Valsartan; Vasodilation

Hypertension and additional non-traditional risk factors can damage the kidney directly and by promoting atherogenesis. Evidence indicates that increased oxidative stress and inflammation may mediate a large part of the effects of risk factors on the kidney. We hypothesized that in hypertensive patients (HT), oxidative stress, measured as 8-ISO-prostaglandin F2alpha (8-ISO-PGF2alpha), should raise paralleling decreasing renal function and should correlate with estimated glomerular filtration rate (eGFR).. In 626 HT with renal function ranging from stages 1 to 5 and 100 healthy controls, plasma levels of 8-ISO-PGF2alpha, high-sensitivity C-reactive protein (CRP), transforming growth factor-beta (TGF-beta) and endothelin-1 (ET-1) were measured. GFR was estimated by the Modification of Diet in Renal Disease study equation.. When HT were stratified according to renal function stages, 8-ISO-PGF2alpha, CRP, TGF-beta and ET-1 increased progressively and significantly with decreasing eGFR. The multiple regression analysis, considering eGFR as a dependent variable, showed that 8-ISO-PGF2alpha (beta = -0.361, P < 0.000001), ET-1 (beta = -0.197, P < 0.0001) and TGF-beta (beta = -0.170, P < 0.0004) correlated independently with eGFR. All biomarkers were good predictors of eGFR <60 ml/min/1.73 m(2) [receiver-operator-curve (ROC) areas]. ET-1 was shown to be the best predictor with a ROC area = 0.938; with a threshold of 4 pg/ml, 91% sensitivity and 85% specificity were observed, whereas 8-ISO had a ROC area = 0.931, and for a threshold of 329 pg/ml, sensitivity and specificity were 89%, respectively. In contrast, CRP showed the lower predictive value with a ROC area = 0.917; with a threshold of 2.52 mg/l, an 87% sensitivity and an 83% specificity were obtained.. Our findings are a clear-cut demonstration of a strong and negative correlation of both oxidative stress and ET-1 with renal function stages in HT. ET-1 and 8-isoprostane are predictive of eGFR.

Topics: Adult; Aged; Atherosclerosis; C-Reactive Protein; Case-Control Studies; Dinoprost; Endothelin-1; Female; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Male; Middle Aged; Oxidative Stress; Renal Insufficiency, Chronic; Risk Factors; Transforming Growth Factor beta

Cardiovascular (CV) diseases are a leading cause of mortality and they are frequent in patients with the obstructive sleep apnea syndrome (OSAS).. In this study we investigated if OSAS influences CV function independently of other CV risk factors frequently present in these patients (e.g. obesity, high blood pressure).. We compared plasma markers of endothelial dysfunction, asymmetric dimethylarginine (ADMA) and endothelin-1 (ET-1), and atherosclerosis progression (soluble fraction of the CD40 ligand, sCD40L) in OSAS patients with (n = 23) and without (n = 18) concurrent CV risk factors, as well as in healthy subjects (n = 23).. Plasma ADMA (p < 0.01) and sCD40L (p < 0.05) were abnormally increased in patients with OSAS versus healthy controls, but they were not influenced by the presence or absence of CV risk factors in OSAS. ET-1 levels were not different between the three groups of subjects studied.. OSAS is associated with endothelial injury and atherosclerosis progression independently of other CV risk factors.

Topics: Adult; Arginine; Atherosclerosis; Cardiovascular Diseases; Case-Control Studies; CD40 Ligand; Endothelin-1; Humans; Male; Middle Aged; Risk Factors; Sleep Apnea, Obstructive

The objective of this study was to evaluate traditional risk factors for cardiovascular disease (CVD) and endothelin-1 (ET-1) levels in Takayasu arteritis (TA) patients. Twenty-two TA patients and 37 controls were evaluated. TA patients had a higher prevalence of hypertension (63.6% vs. 21.6%, p=0.001) and higher levels of triglycerides (129.5 mg/dL+/-70.8 vs. 88.4 mg/dL+/-60.8, p=0.017) than controls. Mean number of CVD risk factors was 1.64+/-1.22 in TA patients and 1.03+/-1.44 among controls, p=0.030. More TA patients presented at least one CVD risk factor when compared to controls (77.2% vs. 51.3%, p=0.048). ET-1 levels were higher in patients than in controls (1.49 pg/mL+/-0.45 vs. 1.27 pg/mL+/-0.32, p=0.034), however no significant difference was found between patients with active and inactive disease. In this study, TA patients presented a higher prevalence of hypertension, higher levels of triglycerides, and ET-1 than controls.

Topics: Adult; Atherosclerosis; Cardiovascular Diseases; Endothelin-1; Female; Humans; Hypertension; Inflammation; Male; Middle Aged; Risk Factors; Takayasu Arteritis; Treatment Outcome; Triglycerides

Mechanisms of air pollution-induced exacerbation of cardiovascular disease are currently unknown, thus we examined the roles of vascular endothelin-1 (ET-1) and reactive oxygen species (ROS) in regulating mediators of vascular remodeling, namely matrix metalloproteinases (MMPs), after exposure to vehicle engine emissions.. ApoE(-/-) mice were exposed by inhalation to filtered air or gasoline engine exhaust (GEE, 1:12 dilution) 6 hours per day for 1 or 7 days. Concurrently, mice were treated with either ET(A) receptor antagonist BQ-123 (100 ng/kg/d) via osmotic minipumps, Tempol (approximately 41 mg/kg/d, orally), or vehicle. GEE-exposure increased vascular MMP-2 and -9, endothelin-1 (ET-1), tissue inhibitor of metalloproteinases (TIMP)-2 mRNA and ROS levels. Aortic MMP protein and plasma MMP-9 were similarly upregulated. GEE-mediated increases in vascular ROS were attenuated by Tempol-treatment, as were MMP-2 and TIMP-2; whereas BQ-123 ameliorated GEE-induced vascular expression of MMP-9, MMP-2, ROS, and ET-1. In a parallel study, diesel exhaust exposure in volunteer human subjects induced significant increases in plasma ET-1 and MMP-9 expression and activity.. These findings demonstrate that acute exposure to vehicular source air pollutants results in upregulation of circulating and vascular factors associated with progression of atherosclerosis, mediated in part through activation of ET-1-ET(A) receptor pathways.

Topics: Administration, Oral; Adolescent; Adult; Animals; Antioxidants; Aorta; Apolipoproteins E; Atherosclerosis; Cyclic N-Oxides; Endothelin-1; Female; Humans; Infusion Pumps, Implantable; Inhalation Exposure; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Knockout; Nitrates; Nitrites; Peptides, Cyclic; Reactive Oxygen Species; Receptor, Endothelin A; RNA, Messenger; Spin Labels; Time Factors; Tissue Inhibitor of Metalloproteinase-2; Up-Regulation; Vehicle Emissions; Young Adult

Endothelial dysfunction plays an important role in the pathogenesis of hypertension. Other risk factors of atherosclerosis also affect its development. The aim of the study was to assess nitric oxide metabolites concentration (nitrites and nitrates No(x)) and endothelin (ET-1) in plasma and cyclic 3,5-guanosine monophosphate (cGMP) in 24 h-urine collection in patients with noncomplicated hypertension without risk factors of atherosclerosis and in hypertensive patients with coronary artery disease (CAD). Sixty-eight subjects were included in the study (44 men, 24 women), aged 47 +/- 76 years, allotted into four groups: I - controls (18 clinically healthy subjects); II - 12 subjects with hypertension without risk factors of atherosclerosis; III - 16 subjects with hypertension and risk factors of atherosclerosis; and IV - 22 subjects with hypertension and CAD. Plasma NO(x) concentration was determined using the Greiss method, plasma ET-1 by ELISA, and urine cGMP using the immunoenzymatic method. Plasma NO(x) concentration was 14.00 +/- 6.88 micromol/L in group I, in group II - 18.62 +/- 5.84 micromol, in group III - 9.96 +/- 4.72 micromol/L, and in group IV - 8.78 +/- 3.72 micromol/L. Statistically significant differences were between groups I and III (p < 0.05) and I and IV (p < 0.04) and groups II and III (p < 0.01) and II and IV (p < 0.01). The concentration of cGMP in 24 h urine collection was in group I - 40 +/- 24 pmol/L; in group II - 54 +/- 41 pmol/L; in group III - 38 +/- 32 pmol/L; and in group IV - 42 +/- 36 pmol/L. There were no significant differences between the groups. Plasma ET-1 concentration was 3.86 +/- 0.52 pg/mL in group I, in group II - 4.05 +/- 0.71 pg/mL, in group III - 4.22 +/- 0.79 pg/mL and in group IV - 4.38 +/- 0.75 pg/mL. Statistically significant differences were between group I and III (p < 0.05), I and IV (p < 0.03), and between group II and IV (p < 0.04). Endothelial dysfunction was not found in hypertensive patients without a family history of cardiovascular diseases and without other risk factors of atherosclerosis. Deterioration of endothelial function was observed in patients with hypertension with risk factors of atherosclerosis. It was most pronounced in those with CAD.

Topics: Aged; Atherosclerosis; Case-Control Studies; Coronary Artery Disease; Cyclic GMP; Endothelin-1; Endothelium, Vascular; Female; Humans; Hypertension; Male; Middle Aged; Nitrates; Nitric Oxide; Nitrites; Risk Factors; Vasodilation

Lipid retention in the vessel wall by glycosaminoglycan (GAG) chains on chondroitin/dermatan sulfate proteoglycans synthesized by vascular smooth muscle cells (VSMC) have recently been established as an early event in human coronary artery atherosclerosis. GAG structure can be altered by growth factors resulting in enhanced binding to low density lipoprotein (LDL). The aim of this study was to determine if proteoglycans produced by endothelin-1 treated VSMCs had increased binding to human LDL, to examine the effect of endothelin-1 on the synthesis and structure of proteoglycans and to elucidate the signalling pathway.. Endothelin-1 stimulated an increase in [(35)S]sulfate and [(3)H]glucosamine incorporation into proteoglycans produced by human VSMC. The increase was due to an increase in GAG chain size assessed by SDS-PAGE and size exclusion chromatography. Increased radiolabel incorporation was inhibited by an ET(A) but not an ET(B) receptor antagonist. Endothelin-1 stimulated an increase in the 6:4 position sulfation ratio on the disaccharides of the GAG chains, an effect that was blocked by bosentan. The EGF receptor antagonist AG1478 did not affect the increase in GAG size mediated by endothelin-1. Inhibition of protein kinase C (PKC) with GF109203X or down regulation by PMA pre-treatment attenuated the effect of endothelin-1 on GAG synthesis.. These data demonstrate that endothelin-1 stimulates changes in GAG chain structure that increase binding to LDL. This action of endothelin-1 may represent a new target for the prevention of lipid binding within the vascular wall and the associated complications resulting from this interaction.

Topics: Atherosclerosis; Coronary Vessels; Dose-Response Relationship, Drug; Endothelin-1; Enzyme Inhibitors; Glycosaminoglycans; Humans; Lipids; Lipoproteins, LDL; Models, Biological; Muscle, Smooth, Vascular; Protein Binding; Proteoglycans; Receptor, Endothelin A; Signal Transduction

To investigate the effects of centipede acidic protein (CAP) on atherosclerotic rats and the mechanisms involved.. Male Sprague-Dawley rats were randomly divided into five groups: control, atherosclerotic, low-dose CAP (L-CAP), high-dose CAP (H-CAP) and simvastatin group (n=12 in each group). Atherosclerotic model was established by a single dose of vitamin D(3) and an atherogenic diet. Rats of H-CAP and simvastatin groups simultaneously received CAP or simvastatin daily for 6 weeks. At the completion of the experiment, the changes in lipid profile, hemorrheology, nitric oxide (NO), endothelin-1 (ET-1), malondialdehyde (MDA) and superoxide desmutase (SOD) were measured, and the histological changes in aorta and liver were observed.. Treatment of atherosclerotic rats with either low or high doses of CAP led not only to significant decreases in plasma total cholesterol, triglyceride, low density lipoprotein and increase in plasma high density lipoprotein, but also to improvement of the hemorrheologic abnormalities. On the other hand, CAP suppressed the lipid peroxidation, regulated the levels of ET-1 and NO. From the histopathological examination, treatment with CAP ameliorated the pathological changes in thoracic aorta and liver in atherosclerotic rats.. These results suggest that CAP significantly suppress the development of atherosclerosis, improves the hemorrheological disturbances and histopathological changes in the atherogenic diet fed rat model. These effects may partly attribute to reverse of dyslipidemia, inhibition of lipid peroxidation, regulation of NO and ET-1 system.

Topics: Acids; Animals; Anticholesteremic Agents; Aorta; Arthropods; Atherosclerosis; Diet, Atherogenic; Disease Models, Animal; Endothelin-1; Hemorheology; Hypolipidemic Agents; Lipid Peroxidation; Lipids; Male; Malondialdehyde; Medicine, Chinese Traditional; Nitric Oxide; Proteins; Rats; Rats, Sprague-Dawley; Simvastatin; Superoxide Dismutase

Endothelin-1 (ET-1) promotes vasoconstriction and cell proliferation, and has been implicated in hypertension and coronary artery disease. Our aim was to analyse the role of the ET-1 gene (EDN1) in the risk for atherosclerosis/myocardial infarction (MI) in a population with smoking as the prevalent risk factor.. The study included 316 patients with early onset MI (<55 years old). All were male with at least one diseased coronary vessel. Denaturing high performance liquid chromatography (DHPLC), single-strand conformation analysis (SSCA), and direct sequencing were used to search for DNA variants in the five EDN1 exons and the promoter region. To determine the association of EDN1 polymorphisms with MI, we genotyped the patients and controls (n=350) and compared the allele and genotype frequencies between groups.. We found six common nucleotide changes: -1394 (T/G) and -974 C/A (promoter), +120 ins/del A (exon 1, 5' UTR), 568 A/G (exon 3, E106E), 844 G/T (exon 5, K198N), and 1617 T/C (exon 5, 3' UTR). No rare EDN1-variants specific to the MIpatients were found. None of the EDN1 polymorphisms were significantly associated with early-onset MI in our population. The two promoter polymorphisms were in linkage disequilibrium with K198N, but no haplotype was associated with MI risk.. In our population, the EDN1 variation did not contribute to early-onset MI.

Topics: Adult; Age of Onset; Aged; Atherosclerosis; Case-Control Studies; DNA Mutational Analysis; Endothelin-1; Exons; Female; Humans; Male; Middle Aged; Myocardial Infarction; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Smoking

Numerous studies have shown that both vasoconstrictive peptide endothelin-1 (ET-1) and inflammatory marker C-reactive protein (CRP) are implicated in the inflammatory process of atherosclerosis. The purpose of the present study was to observe effect of ET-1 on CRP production and the molecular mechanisms in rat vascular smooth muscle cells (VSMCs). The results showed that ET-1 was capable of stimulating VSMCs to produce CRP both in protein and in mRNA levels in vitro and in vivo. ET(A) receptor antagonist BQ123, but not ET(B) receptor antagonist BQ788, inhibited CRP production in VSMCs. In addition, ET-1 was able to elicit reactive oxygen species (ROS) generation and mitogen-activated protein kinase (MAPK) activation, and antioxidant pyrrolidine dithiocarbamate and p38MAPK inhibitor SB203580 inhibited ET-1-induced CRP expression. The results demonstrate that ET-1 induces CPR production in VSMCs via ET(A) receptor followed by ROS and MAPK signal pathway, which may contribute to better understanding of the role of ET-1 in inflammatory activation of the vessel wall during atherogenesis.

Topics: Animals; Atherosclerosis; C-Reactive Protein; Cells, Cultured; Endothelin A Receptor Antagonists; Endothelin-1; Muscle, Smooth, Vascular; p38 Mitogen-Activated Protein Kinases; Peptides, Cyclic; Rats; Reactive Oxygen Species; Receptor, Endothelin A

Instruction. We investigated the correlation between atherosclerosis and tissue and serum levels of endothelin-1 in patients with chronic kidney disease (CKD). MATERIALS AND METHODS. Arterial samples were obtained from 35 patients with CKD during arteriovenous fistula placement. Thirty-one patients with cardiovascular disease who underwent coronary artery bypass graft (CABG) were selected as the atherosclerotic group, and a piece of their aorta punched during CABG was obtained. Also, a small piece of the renal artery was dissected during donation in 24 kidney donors (control group). Tissue endothelin-1 level was measured and atherosclerosis grading was determined by pathologic examination. Serum levels of endothelin-1 were also measured in the three groups. Results. The mean tissue endothelin-1 levels were 10.73+/-7.57 pg/mL, 12.16 +/- 3.95 pg/mL, and 0.93 +/- 1.06 pg/mL in the patients with CKD, those with CABG, and donors, respectively (P < .001). The mean serum endothelin-1 level was 25.23 +/- 15.15 pg/mL in the patients with CKD, 21.13 +/- 17.22 pg/mL in the patients with CABG, and 2.66 +/- 1.51 pg/mL in the donors (P < .001). Atherosclerosis grades correlated with tissue endothelin-1 level (r = 0.823, P < .001) and serum endothelin-1 level (r = 0.608, P < .001) in the patients with CKD. Multiple regression analysis showed tissue endothelin-1 level as the main predicting factor of atherosclerosis (P < .001). CONCLUSIONS. Tissue endothelin-1 concentration is more important than serum endothelin-1 or lipids levels in prediction of atherosclerosis. Thus, blockade of tissue endothelin-1 receptors with its antagonists may prevent atherosclerosis progression.

Topics: Adult; Arteriovenous Shunt, Surgical; Atherosclerosis; Case-Control Studies; Cohort Studies; Endothelin-1; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Risk Factors

The very high carrier frequency of 21-hydroxylase deficiency worldwide has been postulated as indicating a survival advantage. The 'mediators' of such an effect remain speculative.. To look for possible differences in the metabolic and atherogenic risk profile of carriers and noncarriers of CYP21A2 gene mutations at puberty in order to identify possible mediators of the presumed survival advantage for the carriers. It is anticipated that by studying atherogenic risk factors at such an early developmental stage, age-related alterations in these factors may be minimized.. The study group included 45 adolescent girls diagnosed in our center with premature pubarche, 29 of whom were noncarriers and 16 carriers of CYP21A2 mutations. The two groups did not differ in chronological age, age at pubarche or menarche, pubertal stage, body mass index and waist-to-hip ratio. Biochemical and hormonal profile markers as well as markers of endothelial dysfunction were determined by appropriate methodology. Additionally, in each subject, an oral glucose tolerance test and a gonadotrophin-releasing hormone GnRH analogue stimulation test were carried out.. Endothelin-1 values were lower in the carriers compared to the noncarriers (p = 0.031). Higher tissue plasminogen activator and lower plasminogen activator inhibitor-1 values were found in carriers compared to noncarriers (p = 0.02 and <0.001, respectively). The ratio of the insulinogenic index/homeostasis model assessment for insulin resistance, which reflects beta-cell function, was higher in carriers (p = 0.048), indicating a more favorable beta-cell function in the carriers.. Our findings that carriers of CYP21A2 gene mutations have a more favorable internal milieu with regard to the metabolic syndrome and atherogenesis support the theory that heterozygous CYP21A2 mutations provide a survival advantage. The mechanisms involved may be related to the insulin secretion-action pathway, hypothalamic-pituitary-adrenal axis responsiveness or other still unrecognized factors.

Topics: Adolescent; Atherosclerosis; Case-Control Studies; Child; Endothelin-1; Female; Glucose Tolerance Test; Heterozygote; Humans; Hypothalamo-Hypophyseal System; Insulin; Insulin Resistance; Insulin Secretion; Metabolic Syndrome; Mutation; Pituitary-Adrenal System; Plasminogen Activator Inhibitor 1; Risk Factors; Steroid 21-Hydroxylase; Triptorelin Pamoate

Patients with the heterozygous form of familial hypercholesterolemia (FH) display an early onset of atherosclerosis due to disturbed vascular-endothelial function. Whether the improvements of endothelial function after lipid apheresis are mediated by increased NO-production or by an altered turnover of vasoconstrictors such as ET-1 is still unknown. This was the onset of the present study.. Patients with FH and advanced atherosclerosis receiving regular LDL apheresis at 1 to 3 weeks were recruited. Lipids, L-arginine (L-Arg), L-hydroxyarginine (NHA), L-citrulline as well as big endothelin (Big-ET) and endothelin (ET-1) were measured after DALI, HELP and TheraSorb apheresis.. 17 patients with severe FH aged 55.6 years (mean) received a total of 30 treatments. TC, LDL-C, HDL-C, TG and TC / HDL-C ratio were reduced (55, 70, 9, 48, and 52%; p<0.01) with no differences between apheresis systems. L-Arg was reduced after apheresis (HELP -18.0%, DALI -26.5%; Therasorb -7.6%) and returned to baseline after 2 h. Big-ET (p<0.01) and ET-1 were found to be increased directly and 2 hours after apheresis with HELP while transiently decreasing with DALI and Therasorb.. Improvement of endothelial function after apheresis seems to have multifaceted causes. The further elucidation of the interrelationship between endothelial dysfunction and restricted NO synthesis, as addressed in this study by measuring L-NHA, L-Arg, L-Cit, ET-1 and Big-ET will be necessary in the future.

Topics: Adult; Aged; Analysis of Variance; Arginine; Atherosclerosis; Biomarkers; Blood Component Removal; Case-Control Studies; Citrulline; Endothelin-1; Female; Humans; Hyperlipoproteinemia Type II; Lipids; Male; Middle Aged; Nitric Oxide; Pilot Projects; Treatment Outcome

The present study was designed to investigate whether the aqueous extract of rhubarb (AR) could prevent the development of atherosclerosis through regulating vascular inflammatory processes in rats fed with an atherogenic diet. AR significantly reduced plasma low-density lipoprotein-cholesterol, and increased plasma high-density lipoprotein-cholesterol in rats fed with an atherogenic diet. AR inhibited vascular expressions of endothelin-1 (ET-1) and endothelin-converting enzyme (ECE) induced in rats with an atherogenic diet. On the other hand, AR augmented the vascular expression of endothelial nitric oxide synthase (ecNOS) and restored vascular nitric oxide (NO) production. Furthermore, AR suppressed the elevated expression of vascular nuclear factor-kappaB (NF-kappaB) p65 as well as adhesion molecules, including intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin in rats fed with an atherogenic diet. Also, AR decreased endothelial expression of ICAM-1 and ET-1 in aorta. These results suggest that AR suppresses the development of atherosclerosis in the atherogenic-diet rat model through inhibiting vascular expressions of proinflammatory and adhesion molecules via the regulation of nitric oxide and endothelin system.

Topics: Animals; Aorta, Thoracic; Aspartic Acid Endopeptidases; Atherosclerosis; Blood Pressure; Body Weight; Cholesterol, LDL; Diet, Atherogenic; Endothelin-1; Endothelin-Converting Enzymes; Intercellular Adhesion Molecule-1; Male; Metalloendopeptidases; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type III; Plant Extracts; Rats; Rats, Sprague-Dawley; Rheum

Plaque rupture and subsequent embolism as well as thrombosis are major causes of acute myocardial infarction and stroke secondary to atherosclerosis. Pai-1, t-PA, TF and ET-1 are thrombosis- and thrombolysis-related factors which play important roles in thrombosis formation and plaque rupture. Since acute myocardial infarction and stroke are more likely to occur between 6 a.m. and 12 p.m. than at another time of the day, we studied the relationship between circadian rhythm and Pai-1, t-PA, TF and ET-1 in normal and atherosclerotic mice. Atherosclerosis was developed in apoE-/- mice fed a normal diet or a high cholesterol diet. The expression of Pai-1, t-PA, TF and ET-1 in the hearts of control C57BL/6J mice and atherosclerotic mice was measured by real-time RT-PCR at different Zeitgeber times (ZT) including ZT0, ZT4, ZT8, ZT10, ZT12, ZT14, ZT16 and ZT20. The expression of Pai-1, t-PA, TF and ET-1 peaked between ZT14 and ZT16 and bottomed at ZT10 in C57BL/6J mice. Their expression in apoE-/- mice fed a normal diet lost circadian rhythm. Their expression in apoE-/- mice fed a high cholesterol diet peaked at ZT4, indicating a reverse circadian rhythm. Our result indicates that circadian changes in the expression of Pai-1, t-PA, TF and ET-1 may be involved in the onset of myocardial infarction and stroke.

Topics: Animals; Apolipoproteins E; Atherosclerosis; Cholesterol, Dietary; Chronobiology Disorders; Circadian Rhythm; Endothelin-1; Gene Expression; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardium; Plasminogen Activator Inhibitor 1; Thromboplastin; Thrombosis; Tissue Plasminogen Activator

Endothelin is the most potent endogenous vasoconstrictor and is involved in several vascular disorders such as arterial hypertension. Its intense interaction with other vasoactive hormone systems revealed the consideration about the endothelin gene as an interesting candidate for influencing the development of essential hypertension and hypertensive endorgan damage. The purpose of this study was to investigate the role of endothelin-1 Lys198Asn polymorphism in patients with severe arterial hypertension as well as associated endorgan damages.. In 400 hypertensive patients and 150 normotensive controls we examined the endothelin-1 Lys198Asn polymorphism by DNA sequencing and patients were divided according to their genotype (GG, GT, and TT). Moreover, the frequency of endothelin-1 Lys198Asn polymorphism was investigated with respect to the prevalence of several actual or historical endorgan damages (renal disorder, coronary artery disease, vascular events, vascular damage, and congestive heart failure) in hypertensive patients.. Genotype distribution for endothelin-1 Lys198Asn polymorphism was 57.3% (GG), 41.3% (GT), and 1.43% (TT) in normotensive individuals; and in hypertensive individuals was 54.75% (GG), 43% (GT) and 2.25% (TT). Genotype distribution was unaffected in patients with severe hypertension, renal disorder, vascular events, vascular damage, and congestive heart failure. We, however, found a significant difference in hypertensive individuals with coronary artery disease and TT genotype (P=0.004).. Homozygous TT carrier contributes to a higher prevalence of coronary artery disease, especially for three-vessel disease in hypertensive individuals. Thus, the polymorphism at position 198 could serve as a possibility to differentiate high-risk subgroups in the heterogeneous population of hypertensive patients.

Topics: Adult; Aged; Atherosclerosis; Case-Control Studies; Coronary Artery Disease; Endothelin-1; Female; Gene Frequency; Genetic Predisposition to Disease; Heart Failure; Homozygote; Humans; Hypertension; Kidney Diseases; Male; Middle Aged; Polymorphism, Genetic; Risk Factors; Severity of Illness Index

Endothelin (ET)-1 receptor blockade improves endothelial function in the forearm of patients with atherosclerosis. The aim was to investigate whether intracoronary ET receptor blockade improves coronary endothelial function and increases blood flow in patients with coronary artery disease. Ten patients received a 60-minute infusion of either the selective ETA receptor antagonist BQ123 (40 nmol/min, n = 6) or BQ123 + the ETB receptor antagonist BQ788 (40 nmol/min, n = 4). In all patients, substance P, an endothelium-dependent vasodilator, did not increase baseline coronary flow reserve with thermodilution (CFRThermo) (0.71 +/- 0.14 s during NaCl versus 0.59 +/- 0.14 s during substance P) or baseline quantitative coronary angiography (QCA) (2.74 +/- 0.16 mm versus 2.83 +/- 0.20 mm). After ET receptor blockade, however, the response to substance P was significantly improved as determined both by CFRThermo (0.62 +/- 0.14 s during NaCl versus 0.48 +/- 0.10 s during substance P, p < 0.05) and by QCA (2.70 +/- 0.18 mm versus 2.85 +/- 0.19 mm, p < 0.05). In addition, ET blockade increased blood flow in all patients by 16% +/- 10% (n = 10, p < 0.05) and in the BQ123 group by 22% +/- 16% (n = 6, p < 0.05). Furthermore, ETA blockade increased blood flow significantly more than did dual ETA/ETB blockade (p < 0.05). These findings indicate that ET receptor blockade may be a new therapeutic strategy to improve coronary vascular function in patients with coronary artery disease.

Topics: Aged; Aorta, Thoracic; Atherosclerosis; Blood Pressure; C-Reactive Protein; Capillaries; Cardiac Catheterization; Coronary Angiography; Coronary Artery Disease; Coronary Circulation; Coronary Vessels; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Female; Humans; Lipids; Male; Oligopeptides; Peptides, Cyclic; Piperidines

To determine effects of dietary fat content on vascular responses in different conduit arteries in mice.. Vascular responses to reactive oxygen species (ROS)/hydroxyl radical (.OH), acetylcholine (ACh), endothelin-1 (ET-1), and angiotensin II (Ang II) were determined in carotid and femoral arteries of C57BL/6J mice fed with diets varying in fat content (low fat (LF), 12.3%; high fat (HF), 41%; and very high fat (VHF), 58% (kcal from fat)) for 15 weeks, beginning at 4 weeks of age.. In precontracted rings of carotid and femoral artery, ROS/.OH-induced a rapid, transient vasodilation. In the carotid, but not in femoral artery, ROS/.OH-induced dilation increased with increasing dietary fat intake (P < 0.05 vs. LF diet), while contractile responses to ROS/.OH remained unaffected. In femoral arteries, ROS/.OH-induced contractions were reversed into relaxations after both HF and VHF diet (P < 0.05 vs. LF diet). Both ET-1 and Ang II induced strong contractions in the femoral artery that were unaffected by dietary fat intake. In contrast, in the carotid artery Ang II-induced contraction was attenuated after HF and VHF diets (P < 0.005 vs. LF diet), whereas ET-1-induced vasoconstriction was significantly increased (P < 0.05 VHF vs. LF and HF). Treatment with VHF diet enhanced ACh-mediated endothelium-dependent relaxation only in the femoral artery (P < 0.05 vs. HF).. These findings demonstrate that dietary fat content has regional and distinct effects on vascular function in different vascular beds. The data also suggest the possibility that in selected conduit arteries ROS-dependent vasodilator mechanisms become activated in response to increased dietary fat intake.

Topics: Acetylcholine; Angiotensin II; Animals; Atherosclerosis; Carotid Arteries; Dietary Fats; Endothelin-1; Femoral Artery; Hydroxyl Radical; Male; Mice; Mice, Inbred C57BL; Obesity; Reactive Oxygen Species; Vasoconstriction; Vasoconstrictor Agents; Vasodilation

To systematically clarify the effects of apolipoprotein E (aopE) and low-density lipoprotein receptor (LDLR) gene mutant on hyperlipidemia, vascular inflammation impairment and pathogenesis of atherosclerosis (AS), total RNA was isolated from fresh aortas of young apoE/LDLR double knockout (apoE(-/-)/LDLR(-/-)) and wild type (WT) mice using TRIzol reagent. Then RNA was reversely transcribed to first-strand cDNA by reverse transcriptase for reverse transcription polymerase chain reaction (RT-PCR) and real-time RT-PCR. Primer pairs were designed using primer design software according to the gene sequences available in GenBank. β-actin was used as an internal control. Then RT-PCR assay was used to analyze the expression patterns of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), nuclear factor-κB (NF-κB), granulocyte-macrophage colony-stimulating factor (GM-CSF), CD36, endothelin-1 (ET-1), toll-like receptor 2 (TLR2), monocyte chemoattractant protein-1 (MCP-1), vascular adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and platelet-derived growth factor-α (PDGF-α). SYBR Green quantitative real-time RT-PCR was used to validate gene expressions identified by RT-PCR. Blood samples were taken from the retro-orbital venous plexus, and serum levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL) and high-density lipoprotein (HDL) were measured by using biochemical techniques. Serum concentrations of circulating TNF-α, IL-1β and oxidized LDL (ox-LDL) were determined by ELISA. Frozen sections of aortic sinus were stained with Sudan IV to visualize intimal fatty lesions. The results showed that the relative expressions of IL-1β, GM-CSF, ET-1, TLR2, CD36, MCP-1, ICAM-1 and VCAM-1 in apoE(-/-)/LDLR(-/-) mice at the age of 1 month were higher than those in age-matched WT mice (P<0.05, P<0.01), respectively. The expressions of PDGF-α and TNF-α in apoE(-/-)/LDLR(-/-) mice at the age of 2 months were up-regulated compared to those in age-matched WT mice (P<0.05). All the expressions of target genes continued to be up-regulated (P<0.05, P<0.01) except that ET-1 expression at the age of 2 months, TLR2, VCAM-1 and ICAM-1 expressions at the age of 3 months were down-regulated to that in WT mice. NF-κB expression had no significant changes between two genotype mice at different ages. All the gene expressions kept unchanged in WT mice at different ages, except that IL-1b expressions were slightly up-regulated at the age

Topics: Animals; Aorta; Apolipoproteins E; Atherosclerosis; CD36 Antigens; Chemokine CCL2; Endothelin-1; Gene Expression; Granulocyte-Macrophage Colony-Stimulating Factor; Hyperlipidemias; Intercellular Adhesion Molecule-1; Interleukin-1beta; Lipoproteins, LDL; Mice; Mice, Knockout; NF-kappa B; Platelet-Derived Growth Factor; Receptors, LDL; Toll-Like Receptor 2; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

Coronary arteries are the most disease prone arteries in the circulation and are characterized by unique hemodynamic features, wherein wall shear stress (WSS) induced by blood flow and circumferential strain (CS) driven by pressure are highly out-of-phase temporally (asynchronous hemodynamics). To investigate whether there is a correlation between asynchronous hemodynamics and pathology in vivo, we examined endothelial cell (EC) gene expression and nuclear morphology in two distinct hemodynamic regions of male New Zealand rabbits: coronary arteries (left anterior descending artery cLAD), and aorta (aortic arch inner curvature, outer curvature, and straight descending aorta). En face imaging showed strong similarities in EC nuclear length:width ratio and angle of orientation in the cLAD and aorta. Real-time RT-PCR, however, showed that coronary arteries had significantly reduced (>5-fold) eNOS mRNA levels compared to all aortic regions, while ET-1 showed an opposite trend ( approximately 2.5-fold). Coronary arteries with characteristic asynchronous hemodynamics displayed pro-atherogenic eNOS and ET-1 gene expression profiles while the EC nuclei morphology did not differ from non-atherogenic regions in the aorta. This study demonstrates a correlation between asynchronous hemodynamics and pro-atherogenic gene expression patterns in vivo that is induced by hemodynamics inherent to the circulation.

Topics: Animals; Aorta, Thoracic; Atherosclerosis; Coronary Vessels; Endothelial Cells; Endothelin-1; Gene Expression Profiling; Hemorheology; Male; Nitric Oxide Synthase Type III; Rabbits

A strong negative correlation between polyphenols consumption and coronary heart disease has been extensively documented. These results prompted investigations on the mechanisms responsible for polyphenols effects in cardiovascular disease. The aim of this work was to investigate in apoE KO mice the effect of P183/1 (a mixture of cathechin, caffeic acid and resveratrol) on atherosclerosis and gene expression patterns in the vascular wall. ApoE KO mice were fed a diet supplemented with P183/1, 40 and 160 mg/kg body weight/day for 8 weeks. The supplementation with the high dose of P183/1 significantly reduced the presence of atherosclerotic plaque by 40 and 36% in the aortic sinus and in the ascending aorta, respectively. This reduction was associated with a reduced expression of markers for macrophages, lymphocytes (both Th1 and Th2) and of MCP-1, MIP-1alpha, MIP-1beta, CCR1, CCR2 and ET1 in the vascular wall. In conclusion, P183/1 supplementation significantly decreases atherosclerosis in ApoE KO mice by affecting inflammatory cells recruitment and expression of pro-inflammatory chemokines in the vascular wall.

Topics: Animals; Anti-Inflammatory Agents; Aorta; Apolipoproteins E; Atherosclerosis; Caffeic Acids; Cardiovascular Agents; Catechin; Cytokines; Dietary Fats; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin-1; Gene Expression; Mice; Mice, Knockout; Receptors, Chemokine; RNA, Messenger; Stilbenes

Epidemiological evidence indicates that environmental air pollutants are positively associated with the development of chronic vascular disease; however, the mechanisms involved have not been fully elucidated. In the present study we examined molecular pathways associated with chronic vascular disease in atherosclerosis-prone apolipoprotein E-deficient (ApoE(-/-)) mice, including markers of vascular remodeling and oxidative stress, in response to exposure to the ubiquitous environmental pollutant, gasoline engine emissions. ApoE(-/-) mice, on a high-fat diet, were exposed by inhalation to either filtered air; 8, 40, or 60 mug/m(3) particulate matter whole exhaust; or filtered exhaust with gases matching the 60-mug/m(3) concentration, for 7 weeks. Aortas and plasma were collected and assayed for changes in histochemical markers, real-time reverse transcriptase-polymerase chain reaction, and indicators of oxidative damage. Inhalational exposure to gasoline engine emissions resulted in increased aortic mRNA expression of matrix metalloproteinase-3 (MMP-3), MMP-7, and MMP-9, tissue inhibitor of metalloproteinases-2, endothelin-1 and heme oxygenase-1 in ApoE(-/-) mice; increased aortic MMP-9 protein levels were confirmed through immunohistochemistry. Elevated reactive oxygen species were also observed in arteries from exposed animals, despite absence of plasma markers. Similar findings were also observed in the aortas of ApoE(-/-) mice exposed to particle-filtered atmosphere, implicating the gaseous components of the whole exhaust in mediating the expression of markers associated with the vasculopathy. These findings demonstrate that exposure to gasoline engine emissions results in the transcriptional upregulation of factors associated with vascular remodeling, as well as increased markers of vascular oxidative stress, which may contribute to the progression of atherosclerosis and reduced stability of vulnerable plaques.

Topics: Air Pollutants; Animals; Aorta; Apolipoproteins E; Atherosclerosis; Dietary Fats; Endothelin-1; Heme Oxygenase-1; Lung; Male; Metalloproteases; Mice; Mice, Knockout; Oxidative Stress; Reactive Oxygen Species; Transcription, Genetic; Vehicle Emissions

Although local wall shear stress (WSS) induced by blood flow has been implicated in atherogenesis, another prominent and often neglected hemodynamic feature, circumferential strain (CS) driven by pressure, is induced concurrently. To investigate endothelial cell (EC) responses to pathologic hemodynamics and their possible manipulation by pharmaceuticals, we simulated complete hemodynamic conditions comprised of simultaneous WSS and CS during treatment with conjugated linoleic acid (CLA), a known PPAR (-alpha and -gamma) activator and anti-atherogenic agent, on cultured EC and examined effects on gene and metabolite expression. Two hemodynamic conditions representative of distinct regions of the circulation, coronary arteries: pro-atherogenic (asynchronous WSS and CS) and straight descending aorta: non-atherogenic (synchronous WSS and CS), were applied to cultured EC during treatment with the nutraceutical CLA. Competitive-quantitative RT-PCR showed that asynchronous hemodynamics significantly reduced ( approximately 2-fold) eNOS and PPAR-gamma mRNA levels compared to synchronous hemodynamics at 5 and 12 h. ET-1 showed an opposite trend at 12 h. CLA treatment mitigated pro-atherogenic eNOS, ET-1, PPAR-alpha and -gamma mRNA expression profiles and NO and ET-1 secretion patterns during asynchronous hemodynamics. This study demonstrates the potential for a pharmacological treatment (CLA) to normalize pro-atherogenic gene expression profiles induced by hemodynamics inherent to the circulation.

Topics: Animals; Aorta, Thoracic; Atherosclerosis; Cattle; Cells, Cultured; Coronary Vessels; Endothelial Cells; Endothelin-1; Endothelium, Vascular; Linoleic Acids, Conjugated; Nitric Oxide; Nitric Oxide Synthase Type III; PPAR alpha; PPAR gamma; Regional Blood Flow; Shear Strength; Stress, Mechanical

The objective of this article is to investigate the influence of endothelin-1 (ET-1) on human monocyte Na(+)/H(+) exchanger (NHE) activity and on the atherosclerosis-related monocyte functions. ET-1 caused an increase in pHi and in (22)Na influx of monocytes. A reversal of ET-1 effect on pHi was observed in the presence of the NHE1 inhibitor, cariporide. In addition, the activation of NHE1 by ET-1 was mediated via protein kinase C (PKC), mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), and NADPH oxidase. Also, a link between ET-1 and nitric oxide (NO) was observed. Furthermore, after ET-1 treatment, an increase of the adhesive capacity, the migration ability on laminin and CD36 expression of monocytes, was observed; using cariporide this increase was abolished. Our results showed that ET-1 induces a signaling pathway with the involvement of PKC, MAPK, PI3K, and NADPH oxidase where NHE1 plays a key role. ET-1 also plays a significant role in atherosclerosis-related functions of human monocytes, via NHE1 activation.

Topics: Adult; Atherosclerosis; Cation Transport Proteins; Endothelin-1; Humans; Hydrogen-Ion Concentration; Intracellular Fluid; Monocytes; Sodium-Hydrogen Exchanger 1; Sodium-Hydrogen Exchangers

The proinflammatory marker C-reactive protein has been demonstrated to play a role in the development of atherosclerosis. Endothelin-1 and nitric oxide homeostasis is crucial for normal vasomotor function, limiting inflammatory activation and maintaining a nonthrombogenic endothelial surface. In addition to its vasoactive properties, endothelin-1 is also an inflammatory cytokine. We have previously demonstrated that C-reactive protein impairs endothelial cell nitric oxide production. Protein kinase C, an important signal transducer within the cell, is involved in several cellular responses to external stimuli. We therefore sought to determine whether endothelin-1 exposure modulates C-reactive protein's effects on nitric oxide production via protein kinase C.. Endothelial cells were incubated with C-reactive protein (200 microg), endothelin-1 (100 nM), C-reactive protein + endothelin-1, or phosphate-buffered saline solution (control) for 24 hours. After exposure, endothelial nitric oxide synthase expression was determined in addition to total nitric oxide production and protein kinase C translocation and activity.. Endothelial nitric oxide synthase protein expression was reduced following incubation with C-reactive protein and endothelin-1 treatment compared with baseline by 40% and 45%, respectively (P = .04); however, no additive effects were seen with coincubation. C-reactive protein produced a 47% decrease in nitric oxide production compared with control. Coincubation with endothelin-1 resulted in a synergistic 70% reduction in nitric oxide production (P = .001). C-reactive protein exposure inhibited translocation of protein kinase C lambda compared with control (P = .01). Furthermore, coincubation of C-reactive protein with endothelin-1 led to a synergistic inhibition of protein kinase C lambda translocation (P = .01). C-reactive protein exposure reduced protein kinase C activity by 40% compared with control (P = .02), although coincubation with endothelin-1 had a synergistic reduction in activity (P = .02).. Our results indicate that endothelin-1 exposure accentuated C-reactive protein's impairment of endothelial nitric oxide production via synergistic inhibition of protein kinase C lambda translocation and activity. Our investigations suggest that endothelin-1 inhibition and protein kinase C stimulation may provide a novel therapeutic strategy to improve vascular nitric oxide homeostasis and mitigate the proatherosclerotic effects of C-reactive protein.

Topics: Alkaloids; Atherosclerosis; Benzophenanthridines; Bosentan; C-Reactive Protein; Cells, Cultured; Cytokines; Endothelin-1; Endothelium, Vascular; Homeostasis; Humans; Naphthalenes; Nitric Oxide; Nitric Oxide Synthase Type III; Protein Kinase C; Saphenous Vein; Sulfonamides

Endothelin-1 (ET-1) is a potent vasoconstrictive peptide and its activity is mediated by the receptors ET type A (EDNRA) and ET type B (EDNRB). Although ET-1 is thought to play an important role in the development of atherosclerosis, it remains unclear whether polymorphisms of ET-1 family genes, including the ET-1 gene (EDN1), EDNRA, EDNRB and the genes for endothelin converting enzymes 1 and 2 (ECE1 and ECE2), are associated with the progression of atherosclerosis. We investigated the relationship between 11 single nucleotide polymorphisms (SNPs) of ET-1 family genes (including three in EDN1, one in EDNRA, two in EDNRB, four in ECE1 and one in ECE2) and atherosclerotic changes assessed using pulse wave velocity (PWV) and carotid ultrasonography in 630 patients with essential hypertension (EHT). In male subjects, we found significant differences in brachial-ankle PWV (baPWV) in additive and recessive models in EDNRB-rs5351 after Bonferroni correction. Also in male subjects, there were significant differences in mean intima-media thickness (IMT) in additive and recessive models in EDNRA-rs5333 after Bonferroni correction. We found no significant correlation between any SNPs in the ET family genes and baPWV, IMT and Plaque score (PS) in female subjects. Furthermore, after multiple logistic regression analysis, only EDNRB-rs5351 indicated as an independent risk of atherosclerosis in male hypertensive subjects. Of the endothelin-related genes, EDNRB-rs5351 was the most susceptible SNP associated with atherosclerosis in male hypertensives, and the genetic background may be involved in the progression of atherosclerosis in EHT patients.

Topics: Adult; Aged; Atherosclerosis; Disease Progression; Endothelin-1; Female; Humans; Hypertension; Male; Middle Aged; Polymorphism, Single Nucleotide; Pulsatile Flow; Receptor, Endothelin A; Receptor, Endothelin B; Tunica Intima; Tunica Media

Development of a cultured tissue experimental model of rat aorta was explored in order to study mechanism of vascular smooth muscle (VSMC) proliferation. This particular model has potential with regard to amelioration of atherosclerosis and other vascular diseases in comparison to whole animal and cell culture models. The aorta segments of rats were divided into 4 experimental groups: the injured endothelium, injured endothelium plus BQ123, without injured endothelium and without injured endothelium plus BQ123. Each of group was subdivided into a further 2 subgroups and cultured with 20% serum and with serum-free DMEM. Each group cultured in vitro for 5, 8 and 13 days respectively. The control group was not cultured in vitro. Bromodeoxyuridine (BrDU 8x10(-4) mol/l) was added into the cultured medium of all groups, 24 h prior to harvesting. These segments were fixed in 4% paraformaldehyde for paraffin slice used to HE and immunocytochemical staining and other aorta segments were used to detect the expressions of hypertension-related gene-1 (HRG-1) and smooth muscle 22 alpha (SM22alpha) by RT-PCR. ET-1 content in the supernatant was detected with radioimmunology. Proliferous VSMC can be observed on artery segments cultured in vitro, and conspicuous plaques were developed on model vascular wall cultured for 13 days. Labeled cells increased with an increase in culture time but were not seen in the control group. A greater number of labeled cells were observed in injured endothelium group cultured in 20% serum DMEM. Hyperplasia was inhibited after BQ123 was added into the medium, suggesting that serum and ET-1 are important factors that lead to VSMC proliferation. Expressions of HRG-1 and SM22alpha were decreased while the aorta segments were cultured in vitro, minimum or even absent mRNA expressions of HRG-1 and SM22alpha were detected in injured endothelium cultured in 20% serum DMEM and increased in injured endothelium plus BQ123 group cultured. ET-1 content in the supernatant increased in injured endothelium cultured in 20% serum DMEM. These results show that the phenotypic transform and VSMC proliferation on cultured artery segments were related not only to serum culture, but also to ET-1 secreting. ET-1 and serum may be the main factors of contributing to the proliferation and phenotypic transform. This model provides a favorable experimental platform for research into the mechanism of vascular proliferous diseases as well as its prevention and treatment

Topics: Animals; Aorta, Abdominal; Atherosclerosis; Cell Proliferation; Endothelin-1; Male; Models, Biological; Muscle, Smooth, Vascular; Rats; Rats, Sprague-Dawley; Tissue Culture Techniques

Resistin belongs to a family of cysteine-rich secreted polypeptides that are mainly produced by monocytes/macrophages in humans. Recently, high concentrations of resistin were shown to induce vascular endothelial dysfunction and vascular smooth muscle cell proliferation. We examined if resistin was secreted from macrophages locally in atheromas and if it affected vascular cell function in human.. Immunohistochemical staining of human vessels showed that aortic aneurysms exhibited resistin-positive staining areas along macrophage infiltration, while normal arteries and veins did not. Co-localization of resistin and CD68 (a marker for macrophages) was observed in immunofluorescent double staining of aneurysms. Resistin mRNA was expressed much higher in cultured monocytes/macrophages than in human vascular smooth muscle cells (VSMCs) and human umbilical venous endothelial cells (HUVECs). This suggested that the resistin in aneurysms originates from macrophages within the vessels. To determine the effects of resistin on atherosclerosis, HUVECs and human VSMCs were incubated with resistin (10-100 ng/mL for 4 approximately 24 h). In HUVECs, plasminogen activator inhibitor (PAI)-1 release was assayed by ELISA, while the PAI-1 and endothelin (ET)-1 mRNA levels were analyzed by Northern blotting. Both were increased significantly with resistin treatment by factors of 1.3-2.5 (p<0.05). Migratory activity of VSMCs measured by scratched wound assay also increased significantly (1.6 times, p<0.05). In summary, macrophages infiltrating atherosclerotic aneurysms secrete resistin, and resistin affects endothelial function and VSMC migration.. Resistin secreted from macrophages may contribute to atherogenesis by virtue of its effects on vascular endothelial cells and smooth muscle cells in humans.

Topics: Actins; Aged; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Aortic Aneurysm, Abdominal; Atherosclerosis; Cells, Cultured; Endothelial Cells; Endothelin-1; Fluorescent Antibody Technique; Humans; Immunohistochemistry; Macrophages; Male; Middle Aged; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Plasminogen Activator Inhibitor 1; Platelet Endothelial Cell Adhesion Molecule-1; Resistin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Topics: Animals; Atherosclerosis; Cell Proliferation; Endothelial Cells; Endothelin-1; Humans; Mesenteric Arteries; Muscle, Smooth, Vascular; Receptors, Endothelin; Tunica Intima

In this study, basal and thrombin-stimulated release of nitric oxide and endothelin-1 in the internal mammary artery and the radial artery were measured, together with superoxide radicals generated after anoxia and reoxygenation. Arterial segments were obtained from patients undergoing coronary bypass operations. Quantification of nitric oxide was performed by measuring the stable oxidation products of nitric oxide. Endothelin levels were measured by an enzyme immunoassay kit, and the superoxides were measured by lucigenin-enhanced chemiluminescence. Basal and stimulated release of nitric oxide from the internal mammary artery is significantly higher than that in the radial artery. On the other hand, basal release of endothelin-1 is less in the internal mammary artery than in the radial artery, but similar after stimulation. In our study, the quantity of superoxide radicals produced by the internal mammary artery was greater than that produced by the radial artery. Our results show that there are differences between these 2 arteries in regard to production of nitric oxide, endothelin-1, and superoxide radicals. These differences may have a role in the process of atherogenesis and may contribute to long-term patency of arterial bypass grafts. These results may also explain the mechanism of radial artery graft spasm in coronary artery surgery and may constitute a basis for future pharmacological and clinical improvements for successful surgical application.

Topics: Atherosclerosis; Coronary Artery Bypass; Coronary Vasospasm; Endothelin-1; Humans; Luminescence; Mammary Arteries; Nitric Oxide; Radial Artery; Superoxides; Vascular Patency

Endothelin-1 (ET-1) switching in cytokines program and adhesive cascade at atherosclerosis.. 29 patients, suffering from atherosclerosis. The initial ET-1, sCAM: P-, E-selectins, ICAM-1, VCAM-1 levels and IL-1a, IL-1b, IL-6, IL-8 and IL-10 levels and their changes in response to high shear stress (shear rate 100/second, incubation for 6 hours at 37 degrees C) and blood coagulation (incubation at 37 degrees C for 6 hours also) were measured by ELISA kits.. ET-1 level was increased after both tests by unclear mechanisms of its releasing. The increased level of all researched molecules was detected without tests even. After shear stress the sP- and sE-selectins levels were significantly decreased, whereas their levels were strong correlated to ET-1.. We hypothesized that the multiple mechanisms of cell-cell communication were switched on (ET-1 releasing and selctin reinternalization). The ET-1 were closely correlated to proinflammatory cytokines. We postulate that the ET-1 is active participant in cytokine- and sCAM-induced inflammatory repsonse at atherosclerosis.

Topics: Atherosclerosis; Blood Coagulation; Cell Adhesion Molecules; Cytokines; Endothelin-1; Humans; Inflammation; Inflammation Mediators; Stress, Mechanical; Up-Regulation

to analyze to cytokines, sCAM secretion within chromatin topography of lymphocytes at atherosclerosis. Two kinds of response were researched: coagulation (incubation of blood clot within 6 hrs at 37 C) and standardized viscosimetric flow rotational viscosimetr (shear rate 100 -1/s, 60 s at 37 C incubation within 6 hrs at 37 C). ET-1 and sP-, sE-selectin's, sICAM-1 (R&D, UK) were determined by ELISA kits (photometer "Biotech-1000", Beckman, U.S.A.). The chromatin of lymphocyte nuclei was studied using Computer TV Morphodensitometry System "DiaMorph"(Russia) in the smears dyed especially for DNA. After rheological test the decrease of chromatin activity happened. The significant decrease of selectin level's closely correlated to increased of ET-1 level. We observed the deep reorganization of nuclei after the coagulation test (proapoptotic?). ET-1 did not protect lymphocytes from chromatin changes even enchansed the chromatin inactivation. We established that the lymphocytes are the active participants in pro- and antiinflammatory cytokines. We hereby hypothesize that the unclear cell communication mechanisms of observed phenomena were triggered.

Topics: Atherosclerosis; Cell Nucleus; Chromatin Assembly and Disassembly; Cytokines; E-Selectin; Endothelin-1; Epigenesis, Genetic; Humans; Intercellular Adhesion Molecule-1; Lymphocytes; P-Selectin; Up-Regulation