adrenomedullin and Atherosclerosis

Atherosclerosis develops preferentially in areas of the arterial system, in which blood flow is disturbed. Exposure of endothelial cells to disturbed flow has been shown to induce inflammatory signaling, including NF-κB activation, which leads to the expression of leukocyte adhesion molecules and chemokines. Here, we show that disturbed flow promotes the release of adrenomedullin from endothelial cells, which in turn activates its Gs-coupled receptor calcitonin receptor-like receptor (CALCRL). This induces antiinflammatory signaling through cAMP and PKA, and it results in reduced endothelial inflammation in vitro and in vivo. Suppression of endothelial expression of Gαs, the α subunit of the G-protein Gs; CALCRL; or adrenomedullin leads to increased disturbed flow-induced inflammatory signaling in vitro and in vivo. Furthermore, mice with induced endothelial-specific deficiency of Gαs, CALCRL, or adrenomedullin show increased atherosclerotic lesions. Our data identify an antiinflammatory signaling pathway in endothelial cells stimulated by disturbed flow and suggest activation of the endothelial adrenomedullin/CALCRL/Gs system as a promising approach to inhibit progression of atherosclerosis.

Topics: Adrenomedullin; Animals; Atherosclerosis; Blood Circulation; Calcitonin Receptor-Like Protein; Cattle; Cell Adhesion Molecules; Endothelial Cells; Endothelium, Vascular; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Mice; NF-kappa B; Primary Cell Culture; Signal Transduction; Vascular Cell Adhesion Molecule-1

The aim of this study is to compare patients with atherosclerosis and chronic periodontitis and patients who are systemically healthy and chronic periodontitis using alteration of adrenomedullin (ADM), chemokine (C-C motif) ligand 28 (CCL-28), white blood cell levels, platelet levels, high-density lipoprotein, low-density lipoprotein, high-sensitivity C-reactive protein, creatinine, and fibrinogen.. Totally, 40 patients were involved in study; a test group of 20 patients with atherosclerosis-chronic periodontitis and a control group of 20 patients who were nonatherosclerosis-chronic periodontitis. Nonsurgical periodontal treatment was offered to all patients, in whom systemic markers of atherosclerosis were measured in serum; ADM and CCL-28 biomarkers were measured in gingival crevicular fluid.. Systemic markers of atherosclerosis, ADM, and CCL-28 levels have changed significantly in the test group compared to the control group after nonsurgical periodontal treatment.. Treatment of local inflammation and reduction of systemic inflammatory markers are believed to lower the diagnostic criteria for atherosclerosis as well. It is possible to conclude that nonsurgical periodontal treatment of chronic periodontitis, which is a risk factor for atherosclerosis, has a positive effect on the atherosclerosis prognosis.

Topics: Adrenomedullin; Adult; Aged; Atherosclerosis; Biomarkers; C-Reactive Protein; Chemokines, CC; Chronic Periodontitis; Creatinine; Fibrinogen; Gingival Crevicular Fluid; Humans; Leukocyte Count; Lipoproteins, HDL; Middle Aged; Periodontal Index

Endogenous hydrogen sulfide (H2S), a novel gasotransmitter in cardiovascular regulation, plays an important protective role in the development and progression of atherosclerosis (AS). This study was designed to explore the effects of H2S donor on the production of adrenomedullin (ADM) and atrial natriuretic peptide (ANP) in AS rats.. Male Sprague-Dawley rats were randomly divided into control group (n=10), AS group (n=10), and AS+NaHS group (n=10). Rats in the AS and AS+NaHS groups were given 3-day intraperitoneal injections of vitamin D3 and 8-week high-fat diet to induce AS, and the rats in the AS+NaHS group were intraperitoneally injected with H2S donor NaHS. Oil red O staining was applied to detect changes in the areas of the atherosclerotic plaques in the aortic root and the coronary artery; sulfide-sensitive electrode method was used to measure the plasma concentration of H2S. ADM and ANP levels in plasma were determined by radioimmunoassay.. Compared with the control group, marked atherosclerotic plaques were observed in the aortic root and the coronary artery in AS rats. Moreover, plasma H2S level decreased significantly, ADM level increased, and ANP level decreased significantly in AS rats (P<0.01). However, after the treatment with H2S donor NaHS for 8 weeks, the above changes in AS rats were reversed, demonstrated by significantly reduced areas of the atherosclerotic plaques in both the aortic root and the coronary artery, significantly increased plasma H2S level, significantly decreased plasma ADM level, and significantly increased plasma ANP level (P<0.01).. H2S plays an important regulatory effect on vasoactive peptides ADM and ANP in AS rats.

Topics: Adrenomedullin; Animals; Atherosclerosis; Atrial Natriuretic Factor; Hydrogen Sulfide; Male; Rats; Rats, Sprague-Dawley

Adrenomedullin (ADM) is a circulating vasoactive peptide involved in vascular homeostasis and endothelial function. Single nucleotide polymorphisms of the ADM gene are associated with blood pressure variability, and elevated levels of plasma midregional proadrenomedullin (MR-pro-ADM) are associated with cardiovascular diseases.. We investigated the sources of variability of ADM gene expression and plasma MR-pro-ADM concentrations in the general population, and their relationship with markers of atherosclerosis. MR-pro-ADM levels were assessed in 4155 individuals who underwent evaluation of carotid intima-media thickness and arterial rigidity (reflection index and stiffness index). In a subsample of 1372 individuals, ADM gene expression was assessed as part of a transcriptomic study of circulating monocytes. Nongenetic factors explained 45.8% and 7.5% of MR-pro-ADM and ADM expression variability, respectively. ADM expression correlated with plasma C-reactive protein, interleukin-receptor 1A, and myeloperoxidase, whereas MR-pro-ADM levels correlated with C-terminal proendothelin-1, creatinine, and N-terminal pro-B-type natriuretic peptide. Genome-wide association study of ADM expression and MR-pro-ADM levels both identified a single locus encompassing the ADM gene. ADM expression was associated with 1 single nucleotide polymorphism rs11042717 (P=2.36×10(-12)), whereas MR-pro-ADM was associated with 2 single nucleotide polymorphisms with additive effects, rs2957692 (P=1.54×10(-13)) and rs2957717 (P=4.24×10(-8)). Reflection index was independently associated with rs11042717 (P<10(-4)) and ADM expression (P=0.0002) but not with MR-pro-ADM. Weaker associations were observed for stiffness index. Intima-media thickness was not related to ADM single nucleotide polymorphisms or expression.. These results support an involvement of the ADM gene in the modulation of peripheral vascular tone.

Topics: Adrenomedullin; Adult; Aged; Atherosclerosis; Carotid Arteries; Carotid Intima-Media Thickness; Cohort Studies; Female; Gene Expression Profiling; Gene Expression Regulation; Genetic Variation; Genome-Wide Association Study; Genotype; Humans; Linear Models; Male; Middle Aged; Monocytes; Polymorphism, Single Nucleotide; Protein Precursors; Transcription, Genetic; Transcriptome; Vascular Stiffness

This study aimed to explore the effect of onion extract on endogenous hydrogen sulfide (H2S) and adrenomedulin (ADM) and on atherosclerotic progression in rats with atherosclerosis (AS).. Male Sprague-Dawley rats were randomly divided into control, AS and AS+onion groups. Ultrastructure of aorta and atherosclerotic lesions both in aorta and in coronary artery were detected. Plasma and aortic H2S were detected by using a sulfide- sensitive electrode. Plasma and aortic ADM was determined with radioimmunoassay. Cystathionine-γ-lyase (CSE), calcitonin receptor-like receptor (CRLR), receptor activity-modifying protein (RAMP1, RAMP2 and RAMP3) mRNA expressions were analysed. Glutathione peroxidase (GSH-PX), superoxide dismutase (SOD), malondialdehyde (MDA), nitric oxide (NO) and NO synthase (NOS) contents in plasma, SOD1, SOD2 and ICAM-1 expressions in aorta were detected. Rats in the AS group showed marked atherosclerotic lesions both in aorta and in coronary artery but decreased aortic H2S production. Decreased plasma and aortic ADM content, but increased levels of aortic CRLR, RAMP2 and RAMP3 mRNAs were observed. Plasma GSH-PX and SOD were reduced but MDA elevated. Plasma ICAM-1 and NO contents and iNOS activity were increased. Onion extract, however, lessened atherosclerotic lesions and increased endogenous aortic H2S production, but decreased plasma ADM content, aortic ADM content and aortic CRLR, RAMP2 and RAMP3 mRNAs. In addition, it increased plasma GSH-PX level and SOD activities but reduced MDA; it decreased inflammatory response but increased plasma eNOS activity and NO content.. Onion extract exerted a marked antiatherogenic effect in association with the up-regulation of the endogenous CSE/H2S pathway but down-regulation of the ADM/CRLR family in atherosclerotic rats.

Topics: Adrenomedullin; Animals; Aorta; Atherosclerosis; Calcitonin Receptor-Like Protein; Coronary Vessels; Cystathionine gamma-Lyase; Glutathione Peroxidase; Hydrogen Sulfide; Intercellular Adhesion Molecule-1; Male; Malondialdehyde; Microscopy, Electron, Transmission; Onions; Plant Extracts; Rats; Rats, Sprague-Dawley; Receptor Activity-Modifying Protein 1; Receptor Activity-Modifying Protein 2; Receptor Activity-Modifying Protein 3; RNA, Messenger; Superoxide Dismutase; Superoxide Dismutase-1

To assess the association between epicardial adipose tissue thickness (EAT) and plasma adrenomedullin plasma levels in patients with metabolic syndrome (MS).. Twenty-one patients (12 females and 9 males) with MS according to the International Diabetes Federation guidelines, aged 22-58 years, were enrolled into the study and compared to 19 age-matched control subjects without MS. Plasma glucose, lipid, and adrenomedullin levels were assessed. EAT, left ventricular mass, and carotid intima-media thickness were evaluated by transthoracic two-dimensional echocardiography.. No statistically significant differences were found between the groups in age, sex, and height. Body weight, abdominal circumference (AC), body mass index (BMI), systolic blood pressure (SBP), and diastolic blood pressure (DBP) were significantly higher (p=0.0001) in MS patients; this group also showed significantly higher glucose (p=0.001), total cholesterol (p=0.01), LDL-C (p=0.03), VLDL-C (p=0.005), triglyceride (p=0.002), Tg/HDL ratio (p=0.0001), and plasma adrenomedullin (3.49±1.21 vs 1.69±0.92 ng/mL; p=0.0001) levels and lower HDL-C (p=0.02) levels as compared to the control group. EAT was significantly thicker in MS patients compared to the control group (8.45±3.14 vs 5.43±0.96; p=0.0001), showed a positive correlation to BMI (r=0.347; p=0.02), AC (r=0.350; p=0.02), DBP (r=0.346; p=0.02), and adrenomedullin levels (r=0.741; p=0.0001). In multiple linear regression analysis, adrenomedullin was the only parameter associated to EAT (R(2)=0.550; p=0.0001).. In this small patient group, a statistically significant association was found between EAT and plasma adrenomedullin levels, which may be considered as a potential biomarker of MS.

Topics: Adipocytes; Adipose Tissue; Adrenomedullin; Adult; Anthropometry; Atherosclerosis; Biomarkers; Blood Glucose; Carotid Arteries; Female; Humans; Hypertrophy, Left Ventricular; Lipids; Male; Metabolic Syndrome; Middle Aged; Pericardium; Stromal Cells; Ultrasonography; Young Adult

Vascular calcification (VC) is highly associated with increased morbidity and mortality in patients with advanced chronic kidney disease. Paracrine/autocrine factors such as vasoactive peptides are involved in VC development. Here, we investigated the expression of the novel peptide intermedin (IMD) in the vasculature, tested its ability to prevent VC in vivo and in vitro, and examined the mechanism involved.. Rat VC was induced by administration of vitamin D3 plus nicotine (VDN). IMD (100 ng kg(-1) h(-1)) was systemically administered by a mini-osmotic pump. VDN-treated rat aortas showed lower IMD content and increased expression of its receptors, along with increased vascular calcium deposition and alkaline phosphatase (ALP) activity. Low IMD levels were accompanied by increased calcium deposition in human atherosclerotic plaques. In vivo administration of IMD greatly reduced vascular calcium deposition and ALP activity in VDN-treated rats when compared with vehicle treatment, which was further confirmed in cultured vascular smooth muscle cells. Concurrently, the loss of smooth-muscle lineage markers and matrix gamma-carboxyglutamic acid (Gla) protein (cMGP) in aortas was ameliorated by administering IMD to rats with VC, and the increased phosphor-Smad(1/5/8) and core binding factor alpha-1 levels in calcified vasculature were also reduced. However, the inhibitory effects of IMD on VC were eliminated upon pre-treatment with warfarin or small interfering RNA to reduce cMGP.. Reduced endogenous IMD levels are associated with increased mineralization in vivo, and administration of IMD inhibits VC development by increasing cMGP levels. IMD may be an endogenous vasoprotective factor for VC.

Topics: Adrenomedullin; Animals; Aorta; Atherosclerosis; Calcinosis; Calcium-Binding Proteins; Cell Differentiation; Cell Lineage; Disease Models, Animal; Extracellular Matrix Proteins; Humans; Matrix Gla Protein; Muscle, Smooth, Vascular; Neuropeptides; Nicotine; Nicotinic Agonists; Peptide Hormones; Phenotype; Rats; Signal Transduction; Smad Proteins; Vascular Diseases; Vitamin D; Vitamins

Adrenomedullin (ADM) is a multifunctional peptide regulating cardiovascular homeostasis. We studied the role of ADM in the pathogenesis of atherosclerosis by investigating changes in ADM and its receptors - calcitonin receptor-like receptor (CRLR) and receptor activity-modifying proteins (RAMPs) - in aorta of apoE-/- mice and the effect of exogenous ADM administration. ApoE-/- mice were fed an atherogenic diet for 4 weeks, and apoE-/-+ADM mice were additionally given subcutaneous injections of ADM, 300ng/kg/h, for 4 weeks. ApoE-/- mice fed an atherogenic diet showed hyperlipidemia, a large plaque area and increased vessel wall thickness. The mRNA expression and protein level of ADM/ADM receptors were increased in the aorta, compared with C57BL/6J mice. The elevated mRNA level of CRLR and RAMPs correlated positively with ADM mRNA level. Radioimmunoassay revealed a higher plasma and aorta ADM content, by 61.6% and 285% (both P<0.01), respectively, in apoE-/- mice than that in C57BL/6J mice. Exogenous ADM significantly ameliorated dyslipidemia in apoE-/- mice. ADM-treated mice showed fewer aortic plaques, decreased plaque area, by 76% (P<0.01), and reduced ratio of plaque area to luminal area, by 65% (P<0.01), and ultrasonography revealed significantly reduced intima-media thickness of the ascending branch and abdominal aorta. The results suggest that atherosclerotic apoE-/- mice fed an atherogenic diet showed upregulated endogenous ADM and its receptors, and exogenous ADM treatment ameliorated the dyslipidemia and vascular atherosclerotic lesions. ADM/ADM receptors might be an important protective system against atherosclerosis and could become a new target of prevention and therapy for atherosclerosis.

Topics: Adrenomedullin; Animals; Aorta; Apolipoproteins E; Atherosclerosis; Calcitonin Receptor-Like Protein; Diet, Atherogenic; Dyslipidemias; Intracellular Signaling Peptides and Proteins; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptor Activity-Modifying Proteins; Receptors, Adrenomedullin; Receptors, Calcitonin; Receptors, Peptide; RNA, Messenger

Topics: Adrenomedullin; Adult; Age Factors; Aged; Atherosclerosis; Continuous Positive Airway Pressure; Female; Humans; Male; Middle Aged; Polysomnography; Risk Factors; Sex Factors; Sleep Apnea, Obstructive

Topics: Adrenomedullin; Atherosclerosis; Continuous Positive Airway Pressure; Humans; Oxidative Stress; Sleep Apnea, Obstructive

Obstructive sleep apnea syndrome (OSAS) is recognized as one of the risk factors of hypertension and cardiovascular disorders. In the current study, we hypothesized that the hypoxic stress and oxidative stress caused by obstructive sleep apnea would increase circulating adrenomedullin (ADM) levels in untreated OSAS patients as compared to an age and body mass index (BMI)-matched control group and an age-matched, but normal-BMI control group. We further hypothesized that nasal continuous positive airway pressure (nCPAP) treatment may decrease OSAS-induced hypoxic stress, oxidative stress and ADM levels. To examine these hypotheses, we measured circulating ADM and reactive oxygen species (ROS) from leukocytes before and after nCPAP therapy in OSAS patients. The circulating levels of ADM and amount of ROS in untreated OSAS patients were significantly greater than those in the controls. No differences in ADM levels were found between the increased-BMI controls and normal-BMI controls. We observed that nCPAP treatment decreased sleep apneas, nocturnal oxyhemoglobin desaturation, the circulating ADM, and ROS production by leukocytes in OSAS patients. The ADM levels were associated with the magnitude of oxyhemoglobin desaturation rather than the number of sleep apneas. These observations suggest that nCPAP therapy could reduce OSAS-induced nocturnal hypoxemia, generation of ROS, and ADM in patients with OSAS.

Topics: Adrenomedullin; Atherosclerosis; Continuous Positive Airway Pressure; Humans; Hypoxia; Intercellular Adhesion Molecule-1; Leukocytes; Oxidative Stress; Reactive Oxygen Species; Sleep Apnea, Obstructive

Produced by vascular walls, adrenomedullin (AM) exerts antifibrotic actions in the process of cardiovascular remodeling. The purpose of this study was to examine the pathophysiological role of AM in the development of human abdominal aortic aneurysm (AAA).. Immunohistochemical analyses revealed that vascular smooth muscle cells in the media were positive for AM in the early stage of atherosclerotic aorta. Intense immunoreactivity was observed in mast cells of the outer media and adventitia of AAA, and the number of mast cells was greater (p < 0.01) in AAA than in atherosclerotic aorta without any aneurysmal change. To determine the role of AM in mast cells, we examined cultured human mast cell leukemia line-1 (HMC-1) and fibroblasts isolated from AAA patients. Cultured HMC-1 cells were found to express preproAM gene and release AM peptide into the cultured media. When assessed by collagenase-sensitive [3H]proline incorporation and procollagen type I C-peptide secretion, collagen synthesis in co-culture of HMC-1 and the fibroblasts was reduced by 10(-6) mol/L synthetic AM, while conversely, it increased following blockade of the action of endogenous AM with 10 microg/mL anti-AM monoclonal antibody.. The present study suggests an anti-fibrotic role for AM released from mast cells, providing new insight into the biological actions of mast cell-derived AM in the development of AAA.

Topics: Adrenomedullin; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Atherosclerosis; Cell Line, Tumor; Cells, Cultured; Collagen; Fibrosis; Humans; Immunohistochemistry; Mast Cells; Peptides; Protein Biosynthesis; Protein Precursors; Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger