angiotensinogen and Cardiovascular-Diseases

Topics: Angiotensin II; Angiotensin-Converting Enzyme 2; Angiotensinogen; Cardiovascular Diseases; Drug Delivery Systems; Female; Humans; Kidney; Male; Renin; Renin-Angiotensin System; Sodium-Glucose Transporter 2 Inhibitors

The renin-angiotensin-aldosterone system (RAAS) is a well-defined pathway playing a key role in maintaining circulatory homeostasis. Abnormal activation of RAAS contributes to development of cardiovascular disease, including heart failure, cardiac hypertrophy, hypertension, and atherosclerosis. Although several key RAAS enzymes and peptide hormones have been thoroughly investigated, the role of angiotensinogen-the precursor substrate of the RAAS pathway-remains less understood. The study of angiotensinogen single-nucleotide polymorphisms (SNPs) has provided insight into associations between angiotensinogen and hypertension, congestive heart failure, and atherosclerotic cardiovascular disease. Targeted drug therapy of RAAS has dramatically improved clinical outcomes for patients with heart failure, myocardial infarction, and hypertension. However, all such therapeutics block RAAS components downstream of angiotensinogen and elicit compensatory pathways that limit their therapeutic efficacy as monotherapy. Upstream RAAS targeting by an angiotensinogen inhibitor has the potential to be more efficacious in patients with suboptimal RAAS inhibition and has a better safety profile than multiagent RAAS blockade. Newly developed therapeutics that target angiotensinogen through antisense oligonucleotides or silencer RNA technologies are providing a novel perspective into the pathobiology of angiotensinogen and show promise as the next frontier in the treatment of cardiovascular disease.

Topics: Angiotensinogen; Cardiovascular Diseases; Heart Failure; Humans; Hypertension; Oligonucleotides, Antisense; Peptide Hormones; Renin-Angiotensin System; RNA

In recent years, perivascular adipose tissue (PVAT) research has gained special attention in an effort to understand its involvement in vascular function. PVAT is recognized as an important endocrine organ that secretes procontractile and anticontractile factors, including components of the renin-angiotensin-aldosterone system, particularly angiotensinogen (AGT). This review critically addresses the occurrence of AGT in PVAT, its release into the blood stream, and its contribution to the generation and effects of angiotensins (notably angiotensin-(1-7) and angiotensin II) in the vascular wall. It describes that the introduction of transgenic animals, expressing AGT at 0, 1, or more specific location(s), combined with the careful measurement of angiotensins, has revealed that the assumption that PVAT independently generates angiotensins from locally synthesized AGT is incorrect. Indeed, selective deletion of AGT from adipocytes did not lower circulating AGT, neither under a control diet nor under a high-fat diet, and only liver-specific AGT deletion resulted in the disappearance of AGT from blood plasma and adipose tissue. An entirely novel scenario therefore develops, supporting local angiotensin generation in PVAT that depends on the uptake of both AGT and renin from blood, in addition to the possibility that circulating angiotensins exert vascular effects. The review ends with a summary of where we stand now and recommendations for future research.

Topics: Adipose Tissue; Angiotensinogen; Blood Vessels; Cardiovascular Diseases; Humans; Renin-Angiotensin System; Signal Transduction; Vasoconstriction; Vasodilation

Angiotensinogen (AGT) is the unique precursor of all angiotensin peptides. Many of the basic understandings of AGT in cardiovascular diseases have come from research efforts to define its effects on blood pressure regulation. The development of novel techniques targeting AGT manipulation such as genetic animal models, adeno-associated viral approaches, and antisense oligonucleotides made it possible to deeply investigate the relationship between AGT and cardiovascular diseases. In this brief review, we provide contemporary insights into the emerging role of AGT in cardiovascular diseases. In light of the recent progress, we emphasize some newly recognized features and mechanisms of AGT in heart failure, hypertension, atherosclerosis, and cardiovascular risk factors.

Topics: Angiotensinogen; Animals; Blood Pressure; Cardiovascular Diseases; Humans; Oligonucleotides, Antisense

The identification of an alternate extended form of angiotensin I composed of the first twelve amino acids at the N-terminal of angiotensinogen has generated new knowledge of the importance of noncanonical mechanisms for renin independent generation of angiotensins. The human sequence of the dodecapeptide angiotensin-(1-12) [N-Asp

Topics: Adrenal Glands; Angiotensin I; Angiotensin II; Angiotensinogen; Animals; Biocatalysis; Bone Marrow; Brain; Cardiovascular Diseases; Chymases; Gene Expression; Humans; Intestines; Kidney; Myocardium; Peptide Fragments; Rats; Renin-Angiotensin System

The renin-angiotensin system (RAS) is a highly complex hormonal cascade that spans multiple organs and cell types to regulate solute and fluid balance along with cardiovascular function. Much of our current understanding of the functions of the RAS has emerged from a series of key studies in genetically-modified animals. Here, we review key findings from ground-breaking transgenic models, spanning decades of research into the RAS, with a focus on their use in studying blood pressure. We review the physiological importance of this regulatory system as evident through the examination of mouse models for several major RAS components: angiotensinogen, renin, ACE, ACE2, and the type 1 A angiotensin receptor. Both whole-animal and cell-specific knockout models have permitted critical RAS functions to be defined and demonstrate how redundancy and multiplicity within the RAS allow for compensatory adjustments to maintain homeostasis. Moreover, these models present exciting opportunities for continued discovery surrounding the role of the RAS in disease pathogenesis and treatment for cardiovascular disease and beyond.

Topics: Angiotensin-Converting Enzyme 2; Angiotensinogen; Animals; Blood Pressure; Cardiovascular Diseases; Disease Models, Animal; Gene Expression Regulation; Humans; Kidney; Mice; Mice, Knockout; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin; Renin-Angiotensin System; Signal Transduction; Water-Electrolyte Balance

Angiotensinogen (AGT) and aldosterone play key roles in the regulation of blood pressure and are implicated in the pathogenesis of cardiovascular diseases. DNA methylation typically acts to repress gene transcription. The aldosterone synthase gene

Topics: Aldosterone; Angiotensin II; Angiotensinogen; Cardiovascular Diseases; CCAAT-Enhancer-Binding Proteins; Cytochrome P-450 CYP11B2; DNA Methylation; Epigenesis, Genetic; Gene Expression; Gene Expression Regulation; Humans; Hypertension; Promoter Regions, Genetic; Transcription Factors

Topics: Angiotensinogen; Asian People; Cardiovascular Diseases; Case-Control Studies; Genetic Predisposition to Disease; Humans; Polymorphism, Genetic

Topics: Angiotensin II; Angiotensinogen; Animals; Cardiovascular Diseases; Cardiovascular System; Hemodynamics; Humans; Peptidyl-Dipeptidase A; Receptors, Angiotensin; Renin; Renin-Angiotensin System; Signal Transduction; Ventricular Function

The renin-angiotensin system is involved in hypertension and, thus, in cardiac and vascular injury. In general, angiotensin II is considered as the main mediator of this system but angiotensin IIderived peptides were also shown to exert effects in such diseases. Moreover, it became obvious that different cell and corresponding tissue types are characterized by their own renin-angiotensin system. This system is composed of various peptidic derivatives of the precursor angiotensinogen. Those angiotensinogen-derived peptides can be processed further by peptidases and can bind corresponding receptors. Various clinical trials were initiated considering inhibition of the renin-angiotensin system at different stages in cardiac injuries. Recently, a phase 3 trial using infused angiotensin II (LJPC-501) as treatment option in catecholamine-resistent hypotension was established (ClinicalTrials.gov identifier NCT02338843) although it might be that an influence of AngII-derived peptides is not considered. In general, more intense research on AngII-derived peptides should result in novel strategies and therapeutic options in treatment of cardiac and vascular injuries since these peptides exert actions by themselves, some may interfere with AngII-mediated effects, and some can bind different receptors as well. Consequently, they may also become new promising therapeutics in clinical settings in the future. This short review introduces all currently known angiotensins at once, their production and role related to cardiac and vascular injury, which immune cells show renin-angiotensin system components, and how immune cells containing such components might be involved in such diseases as well.

Topics: Angiotensin II; Angiotensinogen; Angiotensins; Cardiovascular Diseases; Clinical Trials, Phase III as Topic; Humans; Hypertension; Renin-Angiotensin System

For many decades, adipose tissue was considered as an inactive body compartment that was only used as an energy store. During the recent years, an increasing amount of data has revealed that adipose tissue is a major endocrine and paracrine organ producing numerous enzymes, hormones and growth factors which are collectively termed as adipokines. Several experimental and clinical studies showed that adipokines modulate insulin sensitivity and have an influence on glucose/fat metabolism and obesity. Apart from these properties, recent research revealed several direct actions of adipokines on endothelial function, vascular homeostasis and atherogenesis which are independent of their effects on glucose and fat metabolism. The present review focuses on the direct effects of adipokines on vascular/endothelial function and atherosclerosis and summarizes the experimental and clinical data which suggest a role for these molecules as potential diagnostic and prognostic cardiovascular markers as well as potential therapeutic target to reduce cardiovascular risk.

Topics: Adipokines; Adiponectin; Angiotensinogen; Animals; Atherosclerosis; Cardiovascular Diseases; Endothelium, Vascular; Gene Expression Regulation; Humans; Insulin; Leptin; Resistin; Tumor Necrosis Factor-alpha

Elevated blood glucose, obesity, high blood pressure, elevated triglycerides and low high density lipoprotein (HDL) cholesterol are well accepted risk factors in the development of coronary artery disease. Clustering of at least three of these factors in an individual is defined as metabolic syndrome (MetS). Obesity is a central pathological mechanism in the disease and it is expected that the incidence of this condition will increase dramatically within the next years. The visceral adipose tissue is not only an energy depot but also an endocrine organ which produces a large number of bioactive molecules, the so called adipokines. In the setting of obesity, the over-production of proinflammatory and pro-thrombotic adipokines is associated with insulin resistance. This mechanism represents the pathophysiological basis for the development of MetS. Inflammation has a central role in the pathogenesis of MetS and in mediating its impact on the development of cardiovascular disease. Knowledge of these mechanisms has relevance in the context of preventive and therapeutic strategies.

Topics: Adiponectin; Adolescent; Adult; Angiotensinogen; Atherosclerosis; Biomarkers; Cardiovascular Diseases; Chemokine CCL2; Endothelium, Vascular; Humans; Inflammation; Insulin Resistance; Interleukin-6; Intra-Abdominal Fat; Leptin; Life Style; Metabolic Syndrome; Obesity; Plaque, Atherosclerotic; Plasminogen Activator Inhibitor 1; Prognosis; Resistin; Risk; Tumor Necrosis Factor-alpha

An association has been shown between plasma renin activity (PRA) and the risk of cardiovascular disease. There is also evidence that angiotensin II exerts detrimental effects on progression and instabilization of atherosclerotic plaque. The renin-angiotensin system (RAS) can be inhibited through inhibition of angiotensin I (Ang I) generation from angiotensinogen by direct renin inhibitors, inhibition of angiotensin II (Ang II) generation from angiotensin I by angiotensin-converting enzyme inhibitors and finally by direct inhibition of the action of Ang II receptor level. Aliskiren, the first direct renin inhibitor to reach the market, is a low-molecular-weight, orally active, hydrophilic nonpeptide. Aliskiren blocks Ang I generation, while plasma renin concentration increases because the drugs blocks the negative feed-back exerted by Ang II on renin synthesis. Because of its long pharmacological half-life, aliskiren is suitable for once-daily administration. Its through-to-peak ratio approximates 98% for the 300 mg/day dose. Because of its mechanism of action, aliskiren might offer the additional opportunity to inhibit progression of atherosclerosis at tissue level. Hypertension is an approved indication for this drug, which is also promising for the treatment of heart failure. The efficacy of this drug in reducing major clinical events is being tested in large ongoing clinical trials.

Topics: Amides; Angiotensinogen; Antihypertensive Agents; Blood Pressure; Cardiovascular Agents; Cardiovascular Diseases; Drug Administration Schedule; Fumarates; Humans; Prorenin Receptor; Protein Precursors; Receptors, Cell Surface; Renin; Renin-Angiotensin System; Treatment Outcome; Vacuolar Proton-Translocating ATPases

Topics: Angiotensinogen; Animals; Blood Pressure; Cardiovascular Diseases; Gene Expression Regulation; Humans; Hypertension; Kidney Diseases; Mutation; Polymorphism, Genetic; Promoter Regions, Genetic; Transcription, Genetic

Cardiovascular diseases rank among the most important mortality causes in the Czech population. Although the unhealthy living style plays a key role in their development and progression, impacts of the hereditary predisposition can not be denied. This article characterizes the gene polymorphisms and results of mutations in general. An overview of the most important findings presented in papers published in the Czech Republic and worldwide follows. Issues of concrete gene polymorphism associations with such pathological conditions as acute or chronic heart failure, essential hypertension or heart rhythm disorders are discussed. Attention is paid to genes that participate on beta-adrenergic signalling, to genes for angiotensin, to ACE-gene and to angiotensin II receptor gene. A table summarizing the most important data is attached to the article.

Topics: Angiotensinogen; Cardiovascular Diseases; Humans; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptors, Adrenergic, beta; Receptors, Angiotensin; Signal Transduction

The concept of local renin-angiotensin systems has been introduced almost 20 years ago to explain the beneficial blood pressure-independent effects of ACE inhibitors and AT(1) receptor antagonists in cardiovascular diseases. In the past decade, research has focussed on the local effects of angiotensin II rather than on the mechanism(s) of its local generation. This review addresses several of the unanswered questions with regard to tissue angiotensin II generation, focussing in particular on the heart and vascular wall: (1) what is the origin of the renin that is required to generate angiotensin II locally, (2) where does tissue angiotensin generation occur (intra- versus extracellular), (3) what is the importance of alternative (non-renin, non-ACE) angiotensin-generating enzymes, (4) do ACE inhibitors and AT(1) receptor antagonists exert local effects that are renin-angiotensin system independent (thereby incorrectly leading to the conclusion that they interfere with the local generation or effects of angiotensin II), and (5) to what degree do differences in tissue angiotensin generation underlie the association between cardiovascular diseases and renin-angiotensin system gene polymorphisms?

Topics: Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Carbohydrate Epimerases; Cardiovascular Diseases; Carrier Proteins; Endopeptidases; Enzyme Precursors; Heart; Humans; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Renin; Renin-Angiotensin System

Essential hypertension affects up to 30% of the adult population; its pathogenesis involves interactions between genetic and environmental factors. Improved understanding of the molecular basis of essential hypertension may facilitate the development of new targeted forms of pharmacological therapy that can be tailored to the needs of individual patients and thereby minimize the risk of morbidity and mortality from cardiovascular diseases. The genetic analysis of complex traits and diseases such as blood pressure and hypertension is difficult because of their polygenic origin, genetic heterogeneity, variable penetrance, unknown modes of inheritance, and variable effects of environmental factors. Molecular variants of the angiotensinogen (AGT) gene, a key component of the renin-angiotensin system, are considered a genetic risk for primary hypertension. Some of the genotypes can be used to identify individual patients who would benefit from a specific anti-hypertensive treatment as well as from a specific life style modification.

Topics: Angiotensinogen; Calmodulin-Binding Proteins; Cardiovascular Diseases; Genotype; Humans; Hypertension; Life Style; Pharmacogenetics; Polymorphism, Single Nucleotide; Receptors, Adrenergic, beta-3; Risk

Topics: Angiotensinogen; Animals; Cardiovascular Diseases; Gene Targeting; Humans; Hypertension; Mice; Mice, Knockout; Peptidyl-Dipeptidase A; Receptors, Angiotensin; Renin; Renin-Angiotensin System

Extensive animal studies and a growing number of human clinical trials have now definitively demonstrated the central role of the renin-angiotensin-aldosterone system in the expression and modulation of cardiovascular disease. In contrast to the original hypothesis, the benefits of angiotensin antagonism do not emanate from the antihypertensive effect alone. Subsequent extensive investigations of angiotensin blockade suggest that the benefits of this approach may also result from the pharmacologic alteration of endothelial cell function and the ensuing changes in the biology of the vasculature. The more recent availability of direct antagonists of the AT(1) angiotensin receptor has introduced an element of doubt into this realm of clinical decision making. The receptor antagonists and the more widely studied converting-enzyme inhibitors share many endpoint attributes. Nevertheless, the partially overlapping mechanisms of action for the two classes of angiotensin antagonists confer distinct pharmacologic properties, including side effect profiles, mechanisms of action, and theoretic salutary effects upon the expression of cardiovascular disease. The current review will attempt to contrast the biology of angiotensin converting-enzyme inhibition with angiotensin II receptor antagonism. A discussion of the differential effects of these drug classes on endothelial cell function and on the modulation of vascular disease will be utilized to provide a theoretic framework for clinical decision making and therapeutics.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Cardiovascular Diseases; Clinical Trials as Topic; Endothelium, Vascular; Humans; Renin-Angiotensin System

Topics: Aldosterone; Angiotensinogen; Animals; Cardiovascular Diseases; Humans; Peptidyl-Dipeptidase A; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Renin; Renin-Angiotensin System

In this meta-analysis, we attempted to derive pooled estimates for the putative associations between various cardiovascular-renal disorders and the M235T polymorphism of the angiotensinogen gene.. Case-control studies were combined, using the Mantel and Haenszel approach. Joint P values for continuous variables were calculated by Stouffer's method. Continuous measurements reported in different units were expressed on a percentage scale using the intrastudy mean of the MM genotype as denominator.. The computerized database used for this analysis included 69 reports with an overall sample size of 27,906 subjects. Overall, possession of the T allele was associated with an increased risk of hypertension. In comparison with the MM reference group (number of studies, n = 32), the excess risk was 31% (P = 0.001) in TT homozygotes and 11% (P = 0.03) in TM heterozygotes. The sensitivity analysis showed that this association was present only in whites (T allelic frequency, f = 42.2%), but not in blacks (f = 77.0%) or Asians (f = 78.0%). Atherosclerotic complications (n = 12), renal microvascular disorders (n = 13), cardiomyopathy (n = 2) or diabetic retinopathy (n = 3) were not correlated with the M235T polymorphism. Publication bias was observed for hypertension, but not for coronary heart disease, including myocardial infarction, and for microvascular nephropathy. Furthermore, in comparison with the MM control group, the circulating angiotensinogen levels (n = 8) were raised by 11 and 7% (P = 0.01) in TT and TM subjects, respectively. In contrast, plasma levels of the angiotensin I converting enzyme (n = 4) and body mass index (n = 15) were not associated with the T allele.. The T allele encoding angiotensinogen is not associated with atherosclerotic or microvascular complications, but in Caucasians behaves as a marker for hypertension. This association, which may have been inflated by publication bias, does not necessarily imply causality.

Topics: Alleles; Angiotensinogen; Asian People; Black People; Cardiovascular Diseases; Case-Control Studies; Cross-Sectional Studies; Female; Genetic Markers; Genotype; Humans; Kidney Diseases; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Risk Factors; White People

The role of molecular genetics in the pathophysiology of various diseases is becoming clearer and clearer. In the field of cardiovascular diseases, molecular genetic aspects have been shown to play a definite role in the aetiology of these diseases. Several molecular-genetic variations called polymorphisms, occur in the population. The genes encoding the different components of the reninangiotensin-aldosterone system (RAAS), an important system in the regulation of the function and structure of the heart and vascular wall, also display polymorphisms. For some of these polymorphisms associations with various cardiovascular and renal diseases have been described. At present, this is particularly clear for the relation between angiotensin-converting-enzyme (ACE) polymorphism and the incidence of atherosclerotic complications and diabetic nephropathy, and for the relation between so-called M235 T-variant of the angiotensinogen gene and hypertension. Future research will have to show where it is worthwhile to use these and other polymorphisms as a marker for genetic risk. In what way the different RAAS-polymorphisms relate to functional abnormalities is as yet unclear, as are the potential therapeutic implications.

Topics: Angiotensin II; Angiotensinogen; Cardiovascular Diseases; Chromosome Mapping; Female; Genetic Markers; Humans; Kidney Diseases; Male; Peptidyl-Dipeptidase A; Point Mutation; Polymorphism, Genetic; Receptors, Angiotensin; Renin-Angiotensin System; Spondylitis, Ankylosing

The involvement of polymorphic variations in the structure of the renin angiotensin aldosterone system genes in the predisposition to cardiovascular disease is a particularly important field of investigation. A large number of studies have been published and their results are often contradictory. It is therefore important to identify the functional variants modifying the level of expression of these genes or the structure of the encoded proteins. This will allow the clear quantitation of their effect on quantitative phenotypes both in vitro and in vivo. It is also important to study in the future new phenotypes, particularly dynamic phenotypes, potentially influenced by these genotypes and to use them for building a new cardio-vascular pharmacogenetics.

Topics: Aldosterone; Angiotensinogen; Cardiovascular Diseases; Genotype; Humans; Kidney Diseases; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptors, Angiotensin; Renin-Angiotensin System

Variations of glucose level represent the major cause of diabetic micro- and macroangiopathy, but other factors play a significant role on the occurrence of the complications, which is difficult to quantify. We will review the genetic factors which modulate vascular and heart response to diabetes. In an attempt to modelize a complex disease, we will distinguish susceptibility gene for the deleterious effects of hyperglycemia, through advanced glycation end-products (AGE), and genes responsible for associated and interacting, diseases, such as hypertension and atherosclerosis. We examine, in particular, the possible interactions of the products of these genes on target organs.

Topics: Angiotensinogen; Cardiovascular Diseases; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Humans; Peptidyl-Dipeptidase A; Receptor, Angiotensin, Type 1; Receptors, Angiotensin

Topics: Angiotensinogen; Animals; Blood Pressure; Cardiovascular Diseases; Female; Humans; Hypertension; Male; Molecular Biology; Peptidyl-Dipeptidase A; Pregnancy; Pregnancy Complications, Cardiovascular; Rats; Renin; Renin-Angiotensin System

The renin-angiotensin system is intimately involved in the control of sodium and water balance, the activity of the sympathetic nervous system, mitogenesis and the regulation of vascular tone. There is evidence that many of these effects may be controlled at a local level by independent tissue renin-angiotensin systems. Drugs that are specific inhibitors of the cascade have proved powerful tools for dissecting the physiology of the renin-angiotensin system, and are of major benefit in the treatment of hypertension and chronic heart failure. Recent evidence suggests that variations in the genes coding for components of the system may affect the risk of developing hypertension and ischaemic heart disease.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Cardiovascular Diseases; Humans; Hypertension; Muscle, Smooth, Vascular; Peptidyl-Dipeptidase A; Renin; Renin-Angiotensin System; Sympathetic Nervous System; Vascular Resistance; Vasoconstriction

Because of its small size, low cost of maintenance, breeding capabilities in captivity, the marmoset, a New World monkey, appears well suited for clinical and fundamental investigations. The contribution of this laboratory animal in the main areas of biomedical research is succinctly described: viral oncology, infections diseases, immunology, reproduction, toxicology and teratology, odontology, behaviour and neuro-psychopathology. Emphasis is put upon the exceptional interest of the use of marmoset as a biological model in cardiovascular studies.

Topics: Angiotensinogen; Animals; Arteriosclerosis; Callitrichinae; Cardiovascular Diseases; Disease Models, Animal; Hypertension; Research

Angiotensin II, through the activation of angiotensin II type 1 receptors, plays a crucial role in atherosclerosis. Statins may interfere with the effects of angiotensin II.. We have investigated the expression of angiotensin II type 1 receptor, angiotensin II type 2 receptor and angiotensinogen on circulating monocytes and T-lymphocytes from subjects at high risk for vascular events before and during simvastatin treatment, and healthy controls. In-vitro experiments were also performed to assess the ability of simvastatin to interfere with angiotensin II signalling.. In comparison with controls, high-risk subjects had similar angiotensin II type 1 receptor expression on the cell membranes but significantly higher angiotensin II type 1 receptor mRNA levels at least in monocyte subsets whereas their expression on T cells was similar. Angiotensin II type 2 receptor mRNA expression was higher than controls in both monocytes and T lymphocytes. No differences were observed in angiotensinogen expression on monocytes while T lymphocytes of high-risk subjects show higher expression. One-month treatment of high-risk subjects with simvastatin resulted in a reduction of angiotensin II type 1 receptor mRNA without affecting angiotensin II type 2 receptor whereas angiotensinogen mRNA expression was reduced at least in monocytes. Incubation in vitro with simvastatin reduces the expression of angiotensin II type 1 receptor mRNA levels on monocytes from untreated subjects.. Simvastatin induces down-regulation of the angiotensin II type 1 receptor, interferes with angiotensin II activity in immune cells and contributes to the anti-inflammatory profile of statins that can explain the therapeutic effects of these drugs.

Topics: Adult; Aged; Angiotensinogen; Cardiovascular Diseases; Case-Control Studies; Female; Flow Cytometry; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Longitudinal Studies; Male; Middle Aged; Monocytes; Polymerase Chain Reaction; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; RNA, Messenger; Simvastatin; T-Lymphocytes

To compare the metabolic and endocrinological effects of estradiol valerate/cyproterone acetate (EV/CPA) to a regimen of conjugated estrogens/medroxyprogesterone acetate (CE/MPA) in postmenopausal women.. Lipid profile, endocrinological parameters, coagulation factors, renin and angiotensinogen were followed in postmenopausal women randomized to EV/CPA or CE/MPA during 12 cycles.. Following 12 cycles of treatment, total plasma cholesterol decreased more with EV/CPA than with CE/MPA. Low-density cholesterol decreased with EV/CPA while it increased with CE/MPA. High-density cholesterol remained fairly unchanged, and triglycerides increased significantly in both groups. Estradiol and estrone levels increased significantly more with EV/CPA than with CE/MPA while the sex-hormone-binding globulin increased more with CE/MPA. Follicle stimulating and luteinizing hormone levels also decreased significantly. Total testosterone and dihydroepiandrosterone sulfate remained stable. Total levothyroxine serum levels increased significantly, but thyroid stimulating hormone and triiodothyronine levels remained stable. Coagulation parameters also remained stable. Angiotensinogen increased, while plasma renin activity and blood pressure remained unchanged.. It is concluded that both EV/CPA and CE/MPA produce favourable metabolic effects. A better lipid profile, compatible with decreased cardiovascular risk, is observed with the EV/CPA regimen. Higher circulating estrogen levels may explain in part this observation.

Topics: Angiotensinogen; Blood Coagulation Factors; Blood Pressure; Cardiovascular Diseases; Cholesterol, HDL; Cholesterol, LDL; Climacteric; Cyproterone Acetate; Energy Metabolism; Estradiol; Estrogen Replacement Therapy; Estrogens, Conjugated (USP); Female; Gonadal Steroid Hormones; Humans; Medroxyprogesterone Acetate; Middle Aged; Renin; Risk Factors

Peripheral arterial diseases (PAD) refer to the arterial diseases other than coronary arteries and the aorta. Atherosclerosis is the major cause of PAD. Renin angiotensin aldosterone system (RAAS)-related genes were associated with cardiovascular diseases. Angiotensin II is the pro-inflammatory, proliferative and vasoconstrictor effector of RAAS in the vascular system.. In this study, we aimed to investigate whether the effects of the angiotensinogen (AGT) rs699 (M268T), angiotensin-converting enzyme (ACE) I/D (rs1799752), angiotensin II receptor type 1 (AGTR1) (A1166C) rs5186, and angiotensin II receptor type 2 (AGTR2) rs35474657 variants were associated with PAD etiology due to atherosclerotic involvement of aorta-iliac and femoro-popliteal artery occlusions.. AGT rs699, AGTR1 rs5186, ACE I/D (rs1799752), AGTR2 rs35474657 gene variants were determined by real-time polymerase chain reaction (RT-PCR) in 63 PAD patients (33 femoro-popliteal, 30 aorta-iliac) and 70 healthy controls.. Although there was no significant relationship in the genotype frequencies of AGT rs699, AGTR1 rs5186, ACE I/D (rs1799752), and AGTR2 rs35474657 variants between PAD and control groups (p > 0.05), AGT rs699 TT genotype was significantly associated with fasting glucose (p = 0.023) in PAD patients. Besides, CC genotype of rs699 was significantly related with HDL-cholesterol levels (p = 0.020) in PAD group. Furthermore, AGTR1 rs5186 CC genotype carriers demonstrated significantly higher LDL-cholesterol (p = 0.034) and triglycerides levels (p = 0.007).. This report is the first to show an association between RAAS-related gene variants and their relation with the biochemical characteristics of PAD and suggests that RAAS-associated gene variants may have significant roles in cardiovascular related phenotypes of PAD patients.

Topics: Angiotensinogen; Atherosclerosis; Cardiovascular Diseases; Female; Genetic Variation; Humans; Male; Middle Aged; Peripheral Arterial Disease; Phenotype; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Risk Factors

Angiotensin II (Ang II: a truncated octapeptide of angiotensinogen, AGT) and 11-β-hydroxylase influence regulation of blood pressure. Dysregulation of Ang II and 11-β-hydroxylase can lead to hypertension and elevate aldosterone levels. Polymorphisms in AGT (encodes AGT) and CYP11B1 (encodes 11-β-hydroxylase) shift the paradigm from physiological to pathological. Currently, various high-throughput techniques are used to genotype these polymorphisms. These techniques require expensive infrastructure and reagents. However, in developing countries, where cost is the main limiting factor, it is not feasible to use expensive techniques. So, the aim of current study was to develop efficient low-cost method for genotyping of cardiovascular disease and hypertension associated polymorphisms of AGT (rs4762, rs5051) and CYP11B1 (rs6410). For this, tetra amplification-refractory mutation system-polymerase chain reaction (T-ARMS-PCR) method was developed and optimized for aforementioned AGT and CYP11B1 gene polymorphisms. Efficiency of T-ARMS-PCR was tested by genotyping 776 human samples. These T-ARMS-PCR assays were also validated by Sanger DNA sequencing, where 100% concordance was found, allowing the efficient use of these T-ARMS-PCR assays for polymorphism genotyping in AGT and CYP11B1 in resource limited settings. T-ARMS-PCR is low-cost, efficient and reliable assay for genotyping of AGT and CYP11B1 gene polymorphisms.

Topics: Alleles; Angiotensin II; Angiotensinogen; Blood Pressure; Cardiovascular Diseases; Female; Gene Frequency; Genotype; Genotyping Techniques; Humans; Hypertension; Male; Peptidyl-Dipeptidase A; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Renin-Angiotensin System; Steroid 11-beta-Hydroxylase

Whether the renin-angiotensin-aldosterone system plays a role or not in the development of cardiovascular morbidity in acromegaly patients is unknown. The aim of the study was to investigate the association between ACE (I/D) and AGT (M235T) gene polymorphisms and cardiovascular and metabolic disorders in the acromegaly.. The study included one hundred and seventeen acromegalic patients (62 F/55 M, age: 50.2 ± 12.3 years) and 106 healthy controls (92 F/14 M, age: 41.4 ± 11.3 years). PCR method was used to evaluate the prevalence of ACE and AGT genotype.. The genotypes of ACE polymorphism in acromegalic patients were distributed as follows; 41.0% (n: 48) for DD, 44.4% (n: 52) for ID and 14.5% (n: 17) for II genotype. The control group had significantly different distribution of the ACE polymorphism [48.1% (n: 51) for DD, 25.5% (n: 27) for ID and 26.4% (n: 28) for II genotype]compared to acromegalic group. Regarding AGT polymorphism, AGT-MT genotype was seen in 88.9% of the acromegalic patients while MM and TT genotype (9.4% and 1.7%, respectively) were present in the rest. The controls had similar distribution of the AGT genotype with the acromegaly group (80.2% MT genotype, 15.1% MM genotype and 4.7% TT genotype). Due to the small number of patients with TT allele (n: 2), T carriers for AGT genotype (AGT-MT+TT) were subgrouped and compared to those with AGT-MM group. ACE-DD, ID and II groups had similar anthropometric measures, blood pressure values and baseline GH and IGF-1 levels. Significantly higher baseline GH levels were found in AGT-MM group compared to T allele carriers [40 (16-60) vs. 12 (5-36) µg/L, p < 0.05]. The compared groups in both polymorphisms had similar fasting plasma glucose levels. Patients with ACE-II genotype had significantly higher HDL-C levels compared to those with ACE-DD and ACE-ID polymorphisms (p < 0.05) whereas there was no significant difference in lipid profile between AGT-MM group and AGT-T allele carriers. Moreover, the compared groups in both polymorphisms had similar distribution of hyperlipidemia, hypertension, impaired glucose metabolism (prediabetes or type 2 diabetes mellitus) and coronary artery disease. In terms of echocardiographic parameters, systolic and diastolic function was similar among the groups in ACE and AGT genotypes. Interestingly, AGT-MM group had higher mitral inflow A. Both ACE (I/D) and AGT (M235T) gene polymorphisms do not seem to have a significant effect on the development of clinical properties or cardiovascular comordities of acromegalic patients.

Topics: Acromegaly; Adult; Angiotensinogen; Cardiomyopathies; Cardiovascular Diseases; Female; Humans; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Renin-Angiotensin System; Risk Factors

A history of placenta-mediated pregnancy complications (PMPCs) increases the risk of cardiovascular disease later in life, possibly related to the persistence of endothelial dysfunction. We performed this study in order to search for a common genetic background shared by women with a history of PMPC and vascular disorders, due to their common pathophysiologic pathway of endothelial dysfunction.. We analyzed the prevalence of seven polymorphisms in ACE, AGTR1, AGT, and eNOS genes, endothelial-function related, in 290 women with a history of premature cardiovascular events (CVDs), and in 367 women with a history of PMPC (preeclampsia (PE), stillbirth (SB), and small for gestational age (SGA)), compared with 300 healthy women (HW) who delivered after uneventful pregnancy (HW).. ACE D allele frequency was similar between women with history of CVD and PMPC, and significantly higher than that observed in HW [OR (95% CI) 1.91, p = 0.002, and OR (95% CI) 2.18, p < 0.0001, respectively]. In women carrying ACE-240T or eNOS-786C allele, a two-fold increase in SB susceptibility was evidenced (p = 0.004 and p = 0.005, respectively). Women with a history of SB and premature CVD exhibited a significantly higher unfavorable allelic burden ≥ 3 in comparison to that observed in HW (p < 0.0001 and p = 0.002, respectively).. Our findings demonstrate a common genetic background shared by women with a history of vascular disorders and PMPCs; pregnancy may be considered a window to future cardiovascular risk; therefore, "non-classic" genetic biomarkers of endothelial dysfunction might allow one to identify women who could have a greater benefit for an early cardiovascular screening and prevention.

Topics: Alleles; Angiotensinogen; Cardiovascular Diseases; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Infant, Small for Gestational Age; Nitric Oxide Synthase Type III; Peptidyl-Dipeptidase A; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Receptor, Angiotensin, Type 1; Risk Factors; Stillbirth

Hyperuricemia is recently reported involving in various obesity-related cardiovascular disorders, especially hypertension. However, the underlying mechanisms are not completely understood. In the present study, we investigated whether uric acid upregulates renin-angiotensin system (RAS) expression in adipocytes. We also examined whether RAS activation plays a role in uric acid-induced oxidative stress in adipocytes. The adipocytes of different phenotypes were incubated with uric acid for 48 h, respectively. Losartan (10(-4) M) or captopril (10(-4) M) was used to block adipose tissue RAS activation. mRNA expressions of angiotensinogen (AGT), angiotensin-converting enzyme-1 (ACE-1), renin, angiotensin type 1 receptor (AT1R), and angiotensin type 2 receptor (AT2R) were evaluated with real-time PCR. Angiotensin II concentrations in supernatant were measured by ELISA. Intracellular reactive species (ROS) levels were measured by fluorescent probe DCFH-DA, DHR, or NBT assay. The uric acid upregulated both RAS (AGT, ACE1, renin, AT1R, and AT2R) mRNA expressions and angiotensin II protein secretion and caused a significant increase in ROS production in 3T3-L1 adipocytes. These effects could be prevented by RAS inhibitors, either losartan or captopril. RAS activation has been causally implicated in oxidative stress induced by uric acid in 3T3-L1 adipocytes, suggesting a plausible mechanism through which hyperuricemia contributes to the pathogenesis of obesity-related cardiovascular diseases.

Topics: 3T3-L1 Cells; Adipocytes; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Antioxidants; Captopril; Cardiovascular Diseases; Mice; Oxidative Stress; Reactive Oxygen Species; Renin-Angiotensin System; Uric Acid

Ex-premature infants are at higher risk for hypertension and cardiovascular disease as adults, although the mechanisms underlying such increased risks are unknown. We hypothesize that postnatal exposure to intermittent hypoxia (IH) leads to cardiovascular dysfunction in adulthood with alterations of the renin-angiotensin pathway.. Neonatal mice were exposed to IH for 4 wk. At the age of 3 mo, various cardiovascular measurements were obtained.. IH-exposed mice exhibited higher systolic blood pressure, impaired baroreflex responses, and decreased heart rate variability. Furthermore, IH-exposed mice manifested evidence of endothelial dysfunction, as shown by reduced reperfusion indices after tail vessel occlusion and impaired vasodilatory responses to acetylcholine. CD31(+) endothelial cells isolated from mesenteric arteries of IH-exposed mice expressed higher levels of angiotensin-converting enzyme and reactive oxygen species; plasma angiotensin-II levels were also significantly higher in these animals. In addition, DNA methylation patterns of the Ace1 and the Agt genes in these cells were congruent with their expression patterns.. Our results suggest that exposures to postnatal IH alter the normal development of the renin-angiotensin system and promote the occurrence of cardiovascular dysfunction during adulthood in mice.

Topics: Age Factors; Angiotensin II; Angiotensinogen; Animals; Animals, Newborn; Baroreflex; Blood Pressure; Cardiovascular Diseases; DNA Methylation; Heart Rate; Hypoxia; Mice; Mice, Inbred C57BL; Renin-Angiotensin System

Low nephron number has been recognised as an important cardiovascular risk factor and recently a strong correlation between renal mass and nephron number has been demonstrated in newborns. The aim of this study was to investigate individual, as well as combined, effects of common variants of genes which encode for major components of the renin-angiotensin system (REN G10601A, AGT G(-6)A, ACE I/D, AGTR1 A1166C) on kidney size in healthy, full-term newborns. A significant additive main effect of the ACE I/D polymorphism, as well as an additive-by-additive interaction between AGT G(-6)A and AGTR1 A1166C variants, were found. The variance attributed to the epistatic effect was 27.9 ml(2)/m(4), which accounted for 73.8% of the interaction variance (37.8 ml(2)/m(4)), 66.4% of the genetic variance (42.0 ml(2)/m(4)) and 4.4% to the total phenotypic variance (628 ml(2)/m(4)). No other statistically significant main or epistatic effects were detected. Our results highlight the importance of considering gene-gene interactions as part of the genetic architecture of congenital nephron number, even when the loci do not show significant single locus effects. Unravelling the genetic determinants of low nephron number, along with early molecular screening, may well help to identify children at risk for cardiovascular disease.

Topics: Angiotensinogen; Cardiovascular Diseases; Epistasis, Genetic; Female; Genetic Predisposition to Disease; Genetic Variation; Humans; Infant, Newborn; Kidney; Male; Models, Genetic; Nephrons; Organ Size; Phenotype; Polymorphism, Single Nucleotide; Quantitative Trait, Heritable; Receptor, Angiotensin, Type 1; Risk Factors

End-stage kidney disease patients continue to have markedly increased cardiovascular disease morbidity and mortality. Analysis of genetic factors connected with the renin-angiotensin system that influences the survival of the patients with end-stage kidney disease supports the ongoing search for improved outcomes.. To assess survival and its association with the polymorphism of renin-angiotensin system genes: angiotensin I-converting enzyme insertion/deletion and angiotensinogen M235T in patients undergoing hemodialysis.. Our study was designed to examine the role of renin-angiotensin system genes. It was an observational study. We analyzed 473 chronic hemodialysis patients in four dialysis units in the state of Rio de Janeiro. Survival rates were calculated by the Kaplan-Meier method and the differences between the curves were evaluated by Tarone-Ware, Peto-Prentice, and log rank tests. We also used logistic regression analysis and the multinomial model. A p value ≤ 0.05 was considered to be statistically significant. The local medical ethics committee gave their approval to this study.. The mean age of patients was 45.8 years old. The overall survival rate was 48% at 11 years. The major causes of death were cardiovascular diseases (34%) and infections (15%). Logistic regression analysis found statistical significance for the following variables: age (p = 0.000038), TT angiotensinogen (p = 0.08261), and family income greater than five times the minimum wage (p = 0.03089), the latter being a protective factor.. The survival of hemodialysis patients is likely to be influenced by the TT of the angiotensinogen M235T gene.

Topics: Adult; Angiotensinogen; Cardiovascular Diseases; Diabetes Complications; Female; Humans; Kaplan-Meier Estimate; Kidney Failure, Chronic; Logistic Models; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Renal Dialysis; Renin-Angiotensin System; Risk Factors; Time Factors

There is a growing need to curate the overwhelming amount of sequencing data which is available in many public databases. For instance, new information shows that the M235T polymorphism at the angiotensinogen gene (AGT) is actually positioned at the position corresponding to the amino acid 268 and not 235. This polymorphism is filled as rs699 in the NCBI SNP database and results in the synthesis of a threonine (T) instead of a methionine (M). It has been widely studied and associated as an important risk factor for several vascular and neuropsychiatric conditions. We faced this new situation during the targeted sequencing of 360 chromosomes from Brazilian subjects studied for the M235T polymorphism, leading to the identification of a novel variation (rs141900991). This report explores the potential impact of such a dinucleotide variation, which promotes the change of alanine (A) to serine (S) at the AGT protein structure (A237S). Considering the previous M268T variation at the four possible haplotypes combined (MA, MS, TA and TS), we performed a comparative hydrophobicity simulation, using the Kyte-Doolittle algorithm, available at the CLB Bio workbench, in the four possible haplotypes. Additional simulations were performed using the programs PolyPhen, I-Mutant and SIFT, in order to evaluate the pathogenicity of both mutations. The predicted hydrophobicity decreases of a similar magnitude, with both MS and TA haplotypes, but the presence of both variations induces a major decrease in hydrophobicity, suggesting a cumulative effect, with possible modifying effect since that this variation per se would limit the hydrophobicity range and the latter chances in finding significant phenotype differences. A better characterization of this kind of variant is particularly important because the current genome wide scan analyses in complex disorders with cardiac or neural etiology are not generating reliable findings, especially if we consider the huge investment with such approach. Additional and unknown variations like this one, with potential modifying effect, might be more common than previously expected.

Topics: Angiotensinogen; Brazil; Cardiovascular Diseases; Databases, Genetic; Genetic Variation; Haplotypes; Humans; Mental Disorders; Polymorphism, Single Nucleotide; Risk Factors

Polycystic ovary syndrome (PCOS) is the most common reproductive dysfunction in premenopausal women. PCOS is also associated with increased risk of cardiovascular disease when PCOS first occurs and later in life. Hypertension, a common finding in women with PCOS, is a leading risk factor for cardiovascular disease. The mechanisms responsible for hypertension in women with PCOS have not been elucidated.. This study characterized the cardiovascular-renal consequences of hyperandrogenemia in a female rat model.. Female Sprague-Dawley rats (aged 4-6 weeks) were implanted with dihydrotestosterone or placebo pellets lasting 90 days. After 10 to 12 weeks, blood pressure (by radiotelemetry), renal function (glomerular filtration rate, morphology, protein, and albumin excretion), metabolic parameters (plasma insulin, glucose, leptin, cholesterol, and oral glucose tolerance test), inflammation (plasma tumor necrosis factor-α), oxidative stress (mRNA expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits, p22(phox), p47(phox), gp91(phox), and NOX4), nitrate/nitrite excretion and mRNA expression of components of the renin-angiotensin system (angiotensinogen, angiotensin-I-converting enzyme [ACE], and AT1 receptor) were determined.. Plasma dihydrotestosterone increased 3-fold in hyperandrogenemic female (HAF) rats, whereas plasma estradiol levels did not differ compared with control females. HAF rats exhibited estrus cycle dysfunction. They also had increased food intake and body weight, increased visceral fat, glomerular filtration rate, renal injury, insulin resistance and metabolic dysfunction, oxidative stress, and increased expression of angiotensinogen and ACE and reduced AT1 receptor expression.. The HAF rat is a unique model that exhibits many of the characteristics of PCOS in women and is a useful model to study the mechanisms responsible for PCOS-mediated hypertension.

Topics: Angiotensinogen; Animals; Blood Glucose; Blood Pressure; Cardiovascular Diseases; Dihydrotestosterone; Disease Models, Animal; Estradiol; Female; Glomerular Filtration Rate; Glucose Tolerance Test; Kidney Diseases; Leptin; Metabolic Syndrome; Oxidative Stress; Polycystic Ovary Syndrome; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System

The Bogalusa Heart Study is a long-term study on cardiovascular disease and has followed a biracial (black/white) population from childhood. Risk factor data pertaining to many patients have been collected over 35 years, and the time course of hypertension has been documented by repeated examinations and measurements. Considerable sex and racial differences have been found to be related to cardiovascular disease. Urinary angiotensinogen (UAGT) is a novel biomarker for the intrarenal activity of the renin-angiotensin system in hypertension and kidney disease. We aimed to determine the relationship of UAGT with traditional cardiovascular disease risk factors in asymptomatic young adults in this biracial population.. We recruited 251 individuals and collected a single random spot urine sample from each one. Because UAGT is significantly increased in diabetic patients and the use of antihypertensive drugs affects UAGT levels, we excluded patients who had diabetes, who were receiving antihypertensive treatment, or both. Consequently, 190 participants were included for this analysis.. UAGT levels did not differ with race or sex, but were significantly correlated with SBP (r = +0.23, P = 0.0015) and DBP (r = +0.24, P = 0.0012). Moreover, high correlations were shown in men, especially in black men (SBP, r = +0.85, P = 0.0005 and DBP, r = +0.72, P = 0.0079). Thus, UAGT is correlated with blood pressure in men, even when they do not show overt proteinuria or albuminuria.. The biomarker, UAGT, may facilitate the identification of individuals that are at increased risk for the development of hypertension and early asymptomatic renal disease.

Topics: Adult; Albuminuria; Angiotensinogen; Black People; Blood Pressure; Cardiovascular Diseases; Humans; Hypertension; Hypotension; Kidney; Longitudinal Studies; Male; Proteinuria; Renin-Angiotensin System; Risk Factors; Urinary Tract; White People

Fructose- or sucrose-rich diets can cause insulin resistance and increase the risk of cardiovascular disease. Adipokines are correlated with the development of these diseases in obesity. We hypothesize that fructose and sucrose induce insulin resistance via effects on adipokine gene expression in adipocytes. This study analyzed the effect of fructose or glucose on adiponectin, haptoglobin, and angiotensinogen gene expression in 3T3-L1 adipocytes. Ten days after differentiation, the cells were pretreated with serum- and glucose-free medium. Twenty-four hours later, fructose or glucose (0, 5, 10, or 20 mmol) was added into the medium, and the cells were collected after a further 24 hours. Adiponectin, haptoglobin, and angiotensinogen gene expression were determined. Adiponectin gene expression increased when 10 or 20 mmol glucose was added compared with that observed for the non-hexose-treated cells. A similar effect occurred when 5 mmol fructose was added. Glucose (10 mmol) and fructose (20 mmol) stimulated haptoglobin gene expression in 3T3-L1 adipocytes compared with 0 mmol, with glucose producing a more pronounced effect. Although 20 mmol fructose caused an increase in angiotensinogen gene expression, glucose did not. In conclusion, in this study of 2 hexoses revealed an increase in adiponectin gene expression, suggesting that the effect of a glucose-rich diet on the development of insulin resistance is not related to the effect of these hexoses on adipocyte adiponectin gene expression. However, insulin resistance and cardiovascular disease promoted by fructose-rich diets could be partially related to the effect of fructose on adiponectin and angiotensinogen gene expression.

Topics: 3T3-L1 Cells; Adipocytes; Adiponectin; Angiotensinogen; Animals; Cardiovascular Diseases; Dietary Sucrose; Fructose; Gene Expression; Glucose; Haptoglobins; Insulin Resistance; Mice; Risk Factors

The aim of this study is to examine whether the ACE-I/D, AGT-M235T, and AT1R-A1166C polymorphisms of the renin-angiotensin system (RAS) genes are associated with cardiovascular and renal-related risk factors in Mexican Americans. Study participants (N = 848) were genotyped by Taqman assays. Association analyses were performed by measured genotype approach. Of the phenotypes examined, the ACE-I/D, AGT-M235T, and AT1R-A1166C polymorphisms exhibited significant association with systolic blood pressure, glomerular filtration rate and body mass index, respectively. The data suggest that the polymorphisms examined in the RAS may modulate the risk factors associated with cardiovascular-renal disease.

Topics: Albuminuria; Alleles; Angiotensinogen; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Gene Frequency; Genetic Variation; Genotype; Humans; Hypertension; INDEL Mutation; Kidney Diseases; Male; Mexican Americans; Peptidyl-Dipeptidase A; Polymorphism, Single Nucleotide; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Risk Factors; Texas

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Cardiovascular Diseases; Cardiovascular System; Humans; Pharmaceutical Preparations; Renin; Renin-Angiotensin System

We investigated whether or not p38 mitogen-activated protein kinase inhibition ameliorates angiotensin II-induced target organ damage. We used double transgenic rats harboring both human renin and angiotensinogen genes (dTGRs). dTGR, with or without p38 inhibitor (BIRB796; 30 mg/kg per day in the diet), and nontransgenic Sprague-Dawley rats were studied in 2 protocols. In protocol 1 (week 7), systolic blood pressure of untreated dTGRs was 204+/-4 mm Hg, but partially reduced after BIRB796 treatment (166+/-7 mm Hg), whereas Sprague-Dawley rats were normotensive. The cardiac hypertrophy index was unchanged in untreated and BIRB796-treated dTGRs. The beta-myosin heavy chain expression of BIRB796-treated hearts was significantly lower in BIRB796 compared with dTGRs, indicating a delayed switch to the fetal isoform. BIRB796 treatment significantly reduced cardiac fibrosis, connective tissue growth factor, tumor necrosis factor-alpha, interleukin-6, and macrophage infiltration. Albuminuria was not reduced in BIRB796-treated dTGRs. Tubular and glomerular damage with tumor necrosis factor-alpha expression was unaltered, although serum creatinine and cystatin C were normalized. Renal macrophage infiltration, fibrosis, and vessel damage were reduced. In protocol 2 (week 8), we focused on mortality and arrhythmogenic electrical remodeling. Mortality of untreated dTGRs was 100% but was reduced to 10% in the BIRB796 group. Cardiac magnetic field mapping showed prolongation of depolarization and repolarization in untreated dTGRs compared with Sprague-Dawley rats with a partial reduction by BIRB796. Programmed electrical stimulation elicited ventricular tachycardias in 81% of untreated dTGRs but only in 48% of BIRB796-treated dTGRs. In conclusion, BIRB796 improved survival, target organ damage, and arrhythmogenic potential in angiotensin II-induced target organ damage.

Topics: Angiotensin II; Angiotensinogen; Animals; Animals, Genetically Modified; Cardiovascular Diseases; Disease Models, Animal; Kidney Diseases; Male; Naphthalenes; p38 Mitogen-Activated Protein Kinases; Protein Kinase Inhibitors; Pyrazoles; Rats; Rats, Sprague-Dawley; Renin

Cardiovascular diseases associated with molecular variants of individual components of renin-angiotensin system are reported to constitute inherited predisposition in humans. Molecular variant frequencies are race- and population-dependent. We examined frequencies of the M235T variant of angiotensinogen gene and I/D polymorphism of gene for angiotensin-converting enzyme in Slovak population: in hypertensive patients, coronary heart disease (CHD), dilated cardiomyopathy (DCM) and myocardial infarction (MI) patients compared to healthy subjects. Frequency of M235T was significantly increased in hypertensive, CHD and DCM patients compared to controls (0.48 and 0.50 vs. 0.40, p < 0.001). Significant increase in D allele frequency compared to controls was observed in the group of patients after MI (0.58 vs. 0.50, p < 0.001), CHD (0.59 vs. 0.50, p < 0.001) and DCM (0.60 vs. 0.50, p < 0.001). These results correlate with other Caucasian populations. In Slovak population, M235T is associated with increased blood pressure and D allele of ACE gene is associated with MI, chronic CHD and DCM, rather than with hypertension. Our results suggest that in Slovak population, D alelle and M235T variant represent a risk factor for several cardiovascular diseases and these polymorphisms might have a cumulative effect on development of cardiovascular diseases.

Topics: Aged; Alleles; Angiotensinogen; Base Sequence; Blood Pressure; Cardiovascular Diseases; Female; Genetic Variation; Genotype; Humans; Male; Middle Aged; Polymerase Chain Reaction; Polymorphism, Genetic; Population Groups; Renin; Renin-Angiotensin System; Risk Factors; Slovakia

Cardiovascular disease (CVD) is a major complication of Type 2 diabetes mellitus. The renin-angiotensin system (RAS) and nitric oxide production are both important regulators of vascular function and blood pressure. Genes encoding proteins involved in these pathways are candidates for a contribution to CVD in diabetic patients. We have investigated variants of the angiotensinogen (AGT), angiotensin converting enzyme (ACE), angiotensin type 1 receptor (AT1R) and endothelial nitric oxide synthase (NOS3) genes for association with subclinical measures of CVD in families with Type 2 diabetes mellitus (T2DM).. Atherosclerosis was measured by carotid intima-media thickness and calcification of the carotid and coronary arteries in 620 European Americans and 117 African Americans in the Diabetes Heart Study. Because of the role of these systems in blood pressure regulation, blood pressure was also investigated.. Compelling evidence of association was not detected with any of the SNPs with any outcome measures after adjustments for covariates despite sufficient power to detect relatively small differences in traits for specific genotype combinations.. Genetic variation of the RAS and NOS3 genes do not appear to strongly influence subclinical cardiovascular disease or blood pressure in this diabetic population.

Topics: Adult; Aged; Aged, 80 and over; Angiotensinogen; Atherosclerosis; Cardiovascular Diseases; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Endothelium; Family Health; Female; Gene Frequency; Humans; Male; Middle Aged; Nitric Oxide Synthase; Peptidyl-Dipeptidase A; Polymorphism, Single Nucleotide; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Risk Factors

Topics: Angiotensinogen; Cardiovascular Diseases; Genetic Predisposition to Disease; Humans; Hypertension; Polymorphism, Genetic; Racial Groups

The M235T mutation of the human angiotensinogen gene has been shown to be associated with elevated circulating angiotensinogen concentrations and essential hypertension. The frequencies of the 235T allele are significantly different in black and white subjects. We analyzed the independent contribution of the angiotensinogen M235T mutation to the development of recurrent coronary events (coronary-related death, nonfatal myocardial infarction, or unstable angina) in a cohort of 916 black (n=145) and white (n=771) postmyocardial infarction patients who were prospectively studied during an average follow-up of 28 months. The frequency of the 235T allele was significantly higher among black (82%) than among white (44%) patients (P<0.001). There was no evidence for Hardy-Weinberg disequilibrium. During follow-up, 41 cardiac events (28%) occurred in blacks and 197 (26%) in whites (P=0.49). Multivariate Cox proportional hazards regression analysis demonstrated that 235T homozygosity was independently associated with increased risk of coronary events among black (hazard ratio: 2.37; P=0.04) but not white (hazard ratio: 0.93; P=0.68) patients, with a significant ethnic-related interaction effect (P for the difference=0.04). Among hypertensive black patients, the TT genotype was associated with a 3.3-fold (P=0.02) increase in the risk of coronary events. Our findings suggest that homozygosity for the 235T mutation in the angiotensinogen gene is an independent risk factor for coronary events in black postmyocardial infarction patients. The presence of hypertension significantly augments the risk associated with this genetic mutation.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Black People; Cardiovascular Diseases; Cohort Studies; Female; Gene Frequency; Genetic Predisposition to Disease; Homozygote; Humans; Hypertension; Male; Methionine; Middle Aged; Myocardial Infarction; Polymorphism, Genetic; Prospective Studies; Recurrence; Threonine; White People

Population blood pressure variation is most likely due to multiple genes. This is likely the reason why monogenic testing with the angiotensinogen (AGT) gene polymorphisms on chromosome 1 (1q42-43), especially M235T, has met with negative results, especially in those of African descent. The RH blood group system, also on chromosome 1 (1 p36.2-34), has likewise been associated with blood pressure variation in African-Americans and with the rise in blood pressure with age in whites. Using a random sample of the population, we investigated the combined effects of single and combined variation of the AGTN M235T and RH genotypes on blood pressure, lipids, and lipoprotein concentrations in Afro-Caribbeans aged 18-60 years from the island nation of Dominica. In monogenic analysis, AGT M235T was not associated with blood pressure. However, it was associated with HDL (MM 42+/-23, MT 44+/-12, TT 52+/-14 (P=0.002)). RH genotype was significantly associated with systolic blood pressure (P=0.006) and Apo-A (P=0.003). These effects remained after adjustment for age, gender, weight, and BMI. In the polygenetic analysis, AGT M235T and RH were significantly associated with systolic blood pressure (P=0.037; interaction effects, P=0.068). The association of the AGT M235T with blood pressure across RH blood group haplotypes was then tested. Of the five RH haplotypes available for analysis, the AGT M235T was significantly associated with blood pressure within the "D" haplotype (P=0.01). The RH blood group and gender were significantly associated with systolic blood pressure and Apo-A levels (P=0.005 and 0.012, respectively). All interactions were independent of age and weight. In conclusion, we demonstrate a significant association of AGT M235T with blood pressure and cholesterol metabolism in an Afro-Caribbean population in the "genetic context" of the RH blood group system. Further investigation of these interactions may help understand the effects of genetic factors on cardiovascular risk in African-derived and other populations.

Topics: Adult; Angiotensinogen; Black People; Blood Pressure; Cardiovascular Diseases; Caribbean Region; Demography; Female; Genotype; Haplotypes; Humans; Lipids; Male; Methionine; Middle Aged; Polymorphism, Genetic; Rh-Hr Blood-Group System; Risk Factors; Threonine

Topics: Adult; Angiotensinogen; Arteriosclerosis; Blood Coagulation; Cardiovascular Diseases; Coronary Angiography; Coronary Disease; Endothelium, Vascular; Genotype; Heat-Shock Proteins; Hemodynamics; Humans; Hypertension; Male; Myocardial Infarction; Nitric Oxide; Platelet Aggregation; Risk Factors; Vasodilation

Conventional and genetic risk factors have been reported to play a role in the pathogenesis of vascular disease, but do not explain the lower burden of cardiac and peripheral vascular disease (PVD) in Chinese compared with Caucasians. The role of renin-angiotensin system (RAS) gene polymorphisms and conventional vascular risk factors has not been determined.. A total of 3097 Chinese diabetic subjects were screened for PVD, which was identified in 194 of the 2967 patients with Type 2 diabetes. Biochemical parameters and the genotype and allele frequencies of three RAS gene polymorphisms, the angiotensin-converting enzyme (ACE) insertion/deletion, angiotensinogen (AGT) M235T and angiotensin II type 1 receptor (AT1R) A1166C polymorphisms were then compared between the PVD patients and 1046 age, gender and diabetes duration-matched patients without PVD.. PVD identified in 6.5% was associated with significantly worse glycaemic control, lipid profile and renal function. Smoking was more common, as were the other macro- and microvascular diseases. The prevalence of hypertension was similar between the groups, yet diastolic blood pressure was slightly lower in the PVD group. The ACE D allele was significantly more frequent in patients with PVD compared with the matched diabetic controls (38.1 vs. 29.8%, P = 0.039). No differences in the AT1R or AGT polymorphisms were observed.. PVD was associated with a worse metabolic profile and greater concomitant vascular disease than controls. The ACE I/D polymorphism was associated with PVD in these Type 2 diabetic patients.

Topics: Aged; Albumins; Angiotensinogen; Blood Glucose; Blood Pressure; Cardiovascular Diseases; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Creatinine; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Gene Deletion; Gene Frequency; Genotype; Hong Kong; Humans; Male; Peptidyl-Dipeptidase A; Peripheral Vascular Diseases; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Triglycerides

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Cardiovascular Diseases; Heart Ventricles; Humans; Peptidyl-Dipeptidase A; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Renin-Angiotensin System; RNA, Messenger

In 76 patients with heart failure (HF) (New York Heart Association [NYHA] classes I through IV) and in 15 control subjects, cardiac angiotensin II (Ang II) generation and its relationship with left ventricular function were investigated by measuring aorta-coronary sinus concentration gradients of endogenous angiotensins and in a part of patients by studying (125)I-labeled Ang I kinetics. Gene expression and cellular localization of the cardiac renin-angiotensin system components, the density of AT(1) and AT(2) on membranes and isolated myocytes, and the capacity of isolated myocytes for synthesizing the hypertrophying growth factors insulin-like growth factor-I (IGF-I) and endothelin (ET)-1 were also investigated on 22 HF explanted hearts (NYHA classes III and IV) and 7 nonfailing (NF) donor hearts. Ang II generation increased with progression of HF, and end-systolic wall stress was the only independent predictor of Ang II formation. Angiotensinogen and angiotensin-converting enzyme mRNA levels were elevated in HF hearts, whereas chymase levels were not, and mRNAs were almost exclusively expressed on nonmyocyte cells. Ang II was immunohistochemically detectable both on myocytes and interstitial cells. Binding studies showed that AT(1) density on failing myocytes did not differ from that of NF myocytes, with preserved AT(1)/AT(2) ratio. Conversely, AT(1) density was lower in failing membranes than in NF ones. Ang II induced IGF-I and ET-1 synthesis by isolated NF myocytes, whereas failing myocytes were unable to respond to Ang II stimulation. This study demonstrates that (1) the clinical course of HF is associated with progressive increase in cardiac Ang II formation, (2) AT(1) density does not change on failing myocytes, and (3) failing myocytes are unable to synthesize IGF-I and ET-1 in response to Ang II stimulation.

Topics: Analysis of Variance; Angiotensin I; Angiotensin II; Angiotensinogen; Cardiomyopathy, Dilated; Cardiovascular Diseases; Chymases; Endothelin-1; Gene Expression; Gene Expression Regulation; Heart Ventricles; Immunohistochemistry; In Situ Hybridization; Insulin-Like Growth Factor I; Iodine Radioisotopes; Myocardial Ischemia; Myocardium; Peptidyl-Dipeptidase A; Platelet-Derived Growth Factor; Protein Precursors; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; RNA, Messenger; Serine Endopeptidases; Ventricular Function, Left

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have effects that extend beyond cholesterol reduction. We used an angiotensin (Ang) II-dependent model to test the hypothesis that cerivastatin ameliorates cardiac injury.. We treated rats transgenic for human renin and angiotensinogen (dTGR) chronically from weeks 4 to 7 with cerivastatin (0.5 mg/kg by gavage). We used immunohistochemistry, electrophoretic mobility shift assays, and reverse transcription-polymerase chain reaction techniques. Compared with control dTGR, dTGR treated with cerivastatin had reduced mortality, blood pressure, cardiac hypertrophy, macrophage infiltration, and collagen I, laminin, and fibronectin deposition. Basic fibroblast growth factor mRNA and protein expression were markedly reduced, as was interleukin-6 expression. The transcription factors NF-kappaB and AP-1 were substantially less activated, although plasma cholesterol was not decreased.. These results suggest that statins ameliorate Ang II-induced hypertension, cardiac hypertrophy, fibrosis, and remodeling independently of cholesterol reduction. Although the clinical significance remains uncertain, the results suggest that statins interfere with Ang II-induced signaling and transcription factor activation, thereby ameliorating end-organ damage.

Topics: Angiotensin II; Angiotensinogen; Animals; Animals, Genetically Modified; Blood Pressure; Cardiovascular Diseases; CD4 Antigens; CD8 Antigens; Collagen; Fibroblast Growth Factor 2; Fibronectins; Gene Expression Regulation; Heart; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunohistochemistry; Interleukin-6; Male; Myocardium; NF-kappa B; Oligonucleotides; Protein Binding; Pyridines; Rats; Rats, Sprague-Dawley; Renin; RNA, Messenger; Survival Analysis; Survival Rate; Transcription Factor AP-1

Topics: Angiotensinogen; Cardiovascular Diseases; Endocrinology; Endothelins; Ghrelin; Humans; Hyperaldosteronism; Hypertension; Mineralocorticoid Receptor Antagonists; Peptide Hormones; Peptides; Peptidyl-Dipeptidase A; Protease Inhibitors

This article investigates the relationship between the polymorphic variations in genes associated with cardiovascular disease and longevity in the Danish population. A new procedure that combines both demographic and the individual genetic information in determining the relative risks of the observed genetic variations is applied. The sex-dependent influences can be found by introducing sex-specific population survival and incorporating the risk of gene-sex interaction. Three genetic polymorphisms, angiotensinogen M/T235, blood coagulation factor VII (FVII) R/Q353 and FVII-323ins10, manifest significant influences on survival in males, with reduced hazards of death for carriers of the angiotensinogen M235 allele, the F VII Q353 allele, and the FVII-323P10 allele. The results show that some of these genotypes associated with lower risk of CVD could also reduce the carrier's death rate and contribute to longevity. However, the presence of sex-dependent effects and the fact that major CVD-associated genes failed to impose detrimental influence on longevity lead us to concur that the aging process is highly complicated.

Topics: Alleles; Angiotensinogen; Cardiovascular Diseases; Denmark; Factor VII; Female; Genetic Variation; Humans; Longevity; Male; Polymorphism, Genetic; Sex Characteristics; Survival Analysis

Genes encoding components of the renin-angiotensin system have been associated with elevated blood pressure (BP) and an increased risk of coronary artery disease. To explore the role of the angiotensinogen (AGT) gene in coronary atherosclerosis and thrombosis, we studied the effect of the AGT M235T gene variant on plasma AGT levels and BP in patients with coronary artery disease and in the subgroup of survivors of myocardial infarction as compared with angiographically defined control subjects.. This was a case-control study of 301 white male subjects examined at Frankfurt University medical center. Plasma AGT levels increased stepwise according to the number of T235 alleles present (no T235 allele, 14.8 +/- 3.9 nmol/L; 1 allele, 15.7 +/- 5.1 nmol/L; 2 alleles, 17.3 +/- 4.7 nmol/L; P =.006). In a multivariate model, circulating AGT emerged as the most important predictor of diastolic pressure (P =.001). In addition, AGT M235T gene polymorphism remained a significant predictor of diastolic BP in a multivariate model adjusted for age, body mass index, fasting glucose, apolipoprotein B, presence of coronary artery disease, and treatment with antihypertensive agents ( P <.05). Finally, homozygosity for T235 was associated with increased univariate risk of coronary artery disease and myocardial infarction (odds ratio estimates 1.5; 95% confidence intervals 1.1 to 2.1, P =.03, and 1.0 to 2.1, P =.05, respectively).. The significant relations observed between the AGT M235T variant, its protein product, and the cardiovascular disease phenotypes provide evidence for a possible role of elevated circulating AGT in the pathogenesis of coronary artery disease.

Topics: Alleles; Angiotensinogen; Blood Pressure; Cardiovascular Diseases; Case-Control Studies; Coronary Artery Disease; Coronary Thrombosis; Gene Frequency; Genotype; Humans; Male; Middle Aged; Multivariate Analysis; Myocardial Infarction; Odds Ratio; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Renin-Angiotensin System; Risk Factors

Greenland Inuit are a population with a low risk of cardiovascular disease. Recently, we stated that frequencies of potentially high risk alleles of the apolipoproteins, fibrinogen, factor V, glycoprotein IIIa and factor VII (FVII) genes have different allele frequencies in the Inuit when compared with Caucasian populations. We have extended this study and evaluated whether or not this was also true for the genetic polymorphisms of tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), angiotensin-converting enzyme (ACE) and angiotensinogen in a group of 133 Greenland Inuit, aged 30-34 gamma. In addition, we compared the plasma levels of these factors and those of C-reactive protein (CRP) and D-Dimer in Inuit and in Danes, comparable for age and gender. Frequencies (f) were assessed of the alleles that are known as the potential high risk alleles in Caucasians. In the Inuit, the f(insertion allele) of the t-PA intron8ins311 polymorphism was 0.37 (CI 0.32-0.43), the f(4G allele) of the PAI-1 promoter polymorphism was 0.88 (CI 0.83-0.91), the f(deletion allele) of the ACE intron16ins287 polymorphism was 0.40 (CI 0.33-0.47) and the f(M-allele) of the angiotensinogen M/T353 polymorphism was 0.30(CI 0.25-0.38). As for fibrinogen and FVII polymorphisms, these frequencies are all significantly different from what is reported for Caucasian populations. In the Inuit, plasma levels of fibrinogen and D-Dimer were higher than in the Danes, the PAI-1 levels were lower and FVII, t-PA and CRP levels were comparable. The observed allele frequencies of the polymorphisms of t-PA, fibrinogen, FVII, ACE, angiotensinogen and the plasma levels of PAI-1 and D-Dimer were in accordance with the low CVD risk in the Inuit, considering the observed associations between these measures and CVD risk in Caucasian populations, but for other measures this was not the case (allele frequencies of the PAI-1 polymorphism, and plasma levels of fibrinogen, FVII and t-PA). In conclusion there are clear differences in genetic background and plasma levels of risk factors in Greenland Inuit compared with Caucasian populations, and these differences were sometimes, but not always, in accordance with the observed low cardiovascular disease risk of the Inuit population.

Topics: Adult; Alleles; Angiotensinogen; Antifibrinolytic Agents; Cardiovascular Diseases; Denmark; DNA; Female; Fibrin Fibrinogen Degradation Products; Greenland; Humans; Inuit; Male; Polymorphism, Genetic; Risk Factors; Vascular Diseases

It has been reported the association between M235T angiotensinogen (AGT) and I/D angiotensin converting enzyme (ACE) gene polymorphisms and hypertension and other cardiovascular risk factors. However there are few data about Spanish population. So that we have studied the relationship among the aforementioned polymorphisms and hypertension and the possibility of association between any polymorphism and a worse cardiovascular risk profile.. 251 hypertensive and 245 control normotensive subjects were studied. The M235T AGT and the I/D ACE gene polymorphisms were determined by polymerase chain reaction (PCR). Family and personal history of cardiovascular disease, lipoprotein profile, microalbuminuria and left ventricular hypertrophy (LVH) by Sokolow index were analyzed in hypertensive patients.. The distribution of the different polymorphisms was similar among hypertensive and normotensive subjects. There was not any relationship among AGT nor ACE genotypes and target organ damage. The II ACE genotype was associated with higher lipoprotein (a) (Lp[a]) levels and greater cerebrovascular disease family history and the MT AGT genotype with lower total cholesterol (TC) and triglycerides (TG) levels.. In our study there was not any relationship between arterial hypertension and M235T AGT or I/D ACE gene polymorphisms. None specific genotype was associated with worse cardiovascular risk profile. The II ACE genotype was a predictor of cerebrovascular disease risk through higher levels of Lp(a) and the MT AGT genotype was associated with a better lipid profile.

Topics: Adult; Angiotensinogen; Cardiovascular Diseases; DNA Probes; Female; Genotype; Humans; Hypertension; Lipids; Male; Middle Aged; Molecular Sequence Data; Peptidyl-Dipeptidase A; Polymerase Chain Reaction; Polymorphism, Genetic; Risk Factors

The renin-angiotensin system regulates blood pressure through its effects on vascular tone, renal hemodynamics, and renal sodium and fluid balance.. Using data from a large population-based sample of 1488 siblings having a mean age of 14.8 years and belonging to the youngest generation of 583 randomly ascertained three-generation pedigrees from Rochester, Minn, we carried out variance components-based linkage analyses to evaluate the contribution of variation in four renin-angiotensin system gene regions (angiotensinogen, renin, angiotensin I-converting enzyme, and angiotensin II receptor type 1) to interindividual variation in systolic, diastolic, and mean arterial pressure. We rejected the null hypothesis that allelic variation in the region of the angiotensin-converting enzyme (ACE) gene does not contribute to interindividual blood pressure variability. After conditioning on measured covariates, variation in this region accounted for 0%, 13% (P=0.04), and 16% (P=0.04) of the interindividual variance in systolic, diastolic, and mean arterial pressures, respectively. These estimates were even greater in a subset of subjects with a positive family history of hypertension (0%, 29% [P=0.005], and 32% [P<0.005], respectively). In sex-specific analyses, genetic variation in the region of the ACE gene significantly influenced interindividual blood pressure variation in males (37% for SBP [P=0.03], 38% for DBP [P=0.04], and 53% for MAP [P<0.005]) but not in females.. Although it is possible that variation in a gene near the ACE gene may explain the observed results, knowledge about the physiological involvement of ACE in blood pressure regulation supports the proposition that the ACE gene itself influences blood pressure variability in a sex-specific manner.

Topics: Adolescent; Angiotensinogen; Blood Pressure; Cardiovascular Diseases; Cohort Studies; Diastole; Disease Susceptibility; Genetic Linkage; Genetic Variation; Genotype; Humans; Hypertension; Male; Microsatellite Repeats; Minnesota; Nuclear Family; Peptidyl-Dipeptidase A; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Renin; Renin-Angiotensin System; Risk Factors; Sampling Studies; Sex Characteristics; Systole; White People

We have developed a transgenic animal model to investigate the effects of overexpression of rat prorenin on the cardiovascular system. Two transgenic rat lines were generated in which rat prorenin expression was directed to the liver by a human alpha1-antitrypsin promoter. Liver-specific expression was confirmed by RNase protection assay. Plasma prorenin concentrations in transgenic rats were increased 400-fold in the males of both lines but were increased only two- to threefold in the females. Thus, transgene expression exhibited sexual dimorphism. Blood pressures were not significantly higher in transgenic rats than in nontransgenic controls. The ratio of heart weight to body weight was greater in male transgenic rats than in the nontransgenic controls. Histological analysis revealed severe renal lesions and hypertrophic cardiomyocytes in transgenic males only. This transgenic model demonstrates a likely role of prorenin in the development of cardiac and renal pathology independent of hypertension. These animals will facilitate studies of the effects of blockade of the renin-angiotensin system and other pharmacological interventions on the development and treatment of cardiac, vascular, and renal lesions induced by changes in this system in the absence of chronic hypertension.

Topics: Angiotensinogen; Animals; Animals, Genetically Modified; Base Sequence; Blood Pressure; Cardiovascular Diseases; Enzyme Precursors; Female; Gene Expression; Heart; Hypertension; Kidney; Liver; Male; Molecular Sequence Data; Organ Size; Rats; Rats, Inbred F344; Renin; Risk Factors; RNA, Messenger

Topics: Adult; Angiotensin II; Angiotensinogen; Animals; Birth Weight; Cardiovascular Diseases; Cephalometry; Eclampsia; Embryonic and Fetal Development; Female; Humans; Hypertension; Infant, Newborn; Pregnancy; Pregnancy Complications, Cardiovascular

Recent epidemiological studies indicate that replacement therapy with oestrogens reduces the cardiovascular risk in postmenopausal women. This protective effect has been ascribed to oestrogen-induced metabolic variations, and notably to the rise of HDL-cholesterol levels observed after oral administration of oestrogens. Recently, long term studies have shown that parenterally administered oestrogens (implants, percutaneous or transdermal administration) have the same effect on blood lipid profile as oral oestrogen over a period of 6 months or more. Factors other than blood lipid changes should be studied in an attempt to elucidate the exact mechanism through which postmenopausal oestrogen administration may reduce the risk of cardiovascular diseases.

Topics: Angiotensinogen; Cardiovascular Diseases; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Estrogen Replacement Therapy; Female; Hemostasis; Humans; Hypertension; Menopause; Triglycerides