adrenomedullin and Arteriosclerosis

Adrenomedullin family includes adrenomedullin (ADM), intermedin (IMD) and different peptide fragments derived from prepro-ADM or prepro-IMD. Recent researches found the interaction between different prepro-peptides or different peptide fragments, which plays a crucial role in maintaining homeostasis of cardiovascular system as well as participates in the occurrence and development of cardiovascular disease. This review intends to introduce cardiovascular effects and pathophysiological significance of adrenomedullin family peptides from function level, receptor level and signaling pathway.

Topics: Adrenomedullin; Animals; Arteriosclerosis; Cardiovascular System; Homeostasis; Humans; Hypertension; Peptide Fragments; Peptide Hormones

Topics: Adrenomedullin; Animals; Arteriosclerosis; Connexins; Cyclooxygenase 2 Inhibitors; Endothelium-Dependent Relaxing Factors; Epoprostenol; Humans; Hypertension; Natriuretic Peptide, C-Type; Nitric Oxide; Nitric Oxide Synthase Type III; Peptides

Adrenomedullin was originally discovered as a vasodilative peptide, but recent studies have revealed its pleiotropic effects. Among these studies, the antioxidative properties of adrenomedullin were observed in adrenomedullin knockout mice. Through its antioxidative effect, adrenomedullin can protect organs from damage induced by high blood pressure, ischemia and aging. This indicates that antioxidants that can inhibit reactive oxygen species production but do not have a scavenging effect could be a new effective therapeutic target for organ protection in hypertension as well as metabolic syndrome, in which higher oxidative stress plays a pivotal role.

Topics: Adrenomedullin; Animals; Antihypertensive Agents; Antioxidants; Arteriosclerosis; Hypolipidemic Agents; Mice; Mice, Knockout; Oxidative Stress; Peptides

Adrenomedullin (AM) is a vasodilator peptide having a wide range of biological actions such as reduction of oxidative stress and inhibition of endothelial cell apoptosis. The AM gene is expressed in vascular walls, and AM was found to be secreted from cultured vascular endothelial cells, smooth muscle cells, and adventitial fibroblasts. Plasma AM levels in patients with arteriosclerotic vascular diseases are elevated in possible association with the severity of the disease. When administered over a relatively short period, AM dilates blood vessels via an endothelium-dependent or independent mechanism. Experiments in vitro have shown that AM exerts multiple actions on cultured vascular cells, which are mostly protective or inhibitory against vascular damage and progression of arteriosclerosis. Either prolonged infusion or overexpression of AM suppressed intimal thickening, fatty streak formation, and perivascular hyperplasia in rodent models for vascular remodeling or atherosclerosis. Intimal thickening induced by periarterial cuff was more severe in AM gene-knockout mice than their littermates, suggesting a protective role for endogenous AM. Moreover, AM has recently been suggested to possess angiogenetic properties. Collectively, a body of evidence suggests that AM participates in the mechanism against progression of vascular damage and remodeling, thereby alleviating the ischemia of tissues and organs.

Topics: Adrenomedullin; Amino Acid Sequence; Animals; Arteriosclerosis; Blood Vessels; Humans; Molecular Sequence Data; Peptides; Vasodilation

Topics: Adrenomedullin; Arteriosclerosis; Diagnostic Techniques, Endocrine; Heart Failure; Humans; Hypertension; Immunoradiometric Assay; Kidney Failure, Chronic; Peptides; Radioimmunoassay; Reference Values; Shock, Septic; Specimen Handling; Systemic Inflammatory Response Syndrome

Topics: Adrenomedullin; Animals; Arteriosclerosis; Biomarkers; Body Fluids; Cardiovascular Diseases; Cardiovascular System; Cell Division; Glomerular Mesangium; Hemodynamics; Humans; Kidney Failure, Chronic; Kidney Tubules, Distal; Myocardial Infarction; Peptides; Renal Circulation; Renal Dialysis; Sodium; Ventricular Remodeling

Topics: Adrenomedullin; Animals; Arteriosclerosis; Biomarkers; Cardiovascular Physiological Phenomena; Humans; Neovascularization, Physiologic; Oxidative Stress; Peptides

Topics: Adrenomedullin; Animals; Arteriosclerosis; Blood Vessels; Cell Division; Endothelial Cells; Humans; Neovascularization, Physiologic; Peptides; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Regeneration; Regenerative Medicine

Adrenomedullin (ADM) is a vasoreactive physiological peptide with anti-inflammatory effects and vasodilative and immunomodulatory actions that is widely distributed throughout the vascular system of the brain.. To investigate mid-regional proADM (MR-proADM), a stable fragment of the ADM precursor, and cerebral deep white matter lesions (DWMLs) in association with cognitive decline.. The study participants were 288 patients (194 men, 94 women) who gave consent to participate in a 5-year longitudinal survey on arteriosclerosis from 2008 to 2013. The Fazekas classification system (Grade [G] 0 [normal] to G3 [severe]) was used for the evaluation of DWMLs on brain magnetic resonance imaging (MRI). In addition, all participants were asked to undergo cognitive function tests regarding word/letter fluency, the results of which were assessed for correlations with MR-proADM levels.. MR-proADM levels significantly increased with DWML grade progression. The odds ratio for high MR-proADM levels was 3.08 (95% confidence interval: 1.49-5.17) in the groups graded G3 on brain MRI, suggesting that a high level of MR-proADM is an independent risk factor for DWMLs. A significant inverse correlation was observed between MR-proADM levels and cognitive test scores. MR-proADM levels were significantly increased in the G3 group in 2013 compared with 2008.. MR-proADM levels were significantly different between the DWML groups and inversely correlated with cognitive function test scores, suggesting that high MR-proADM levels and DWMLs are associated with cognitive decline. Therefore, the MR-proADM level may be an effective candidate as a potential diagnostic surrogate marker of cognitive decline.

Topics: Adrenomedullin; Aged; Arteriosclerosis; Biomarkers; Brain; Cognitive Dysfunction; Disease Progression; Female; Follow-Up Studies; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Protein Precursors; Risk Factors; White Matter

Adrenomodulin (ADM) is a peptide hormone secreted in response to cellular strain such as ischemia and is believed to have a beneficial effect on the cardiovascular system. However, the epidemiological relationships between ADM and measurements of haemodynamics, arteriosclerosis and atherosclerosis are not well established. The aim of this study was to investigate the association between the mid-regional part of pro-ADM (MR-proADM) and brachial pulse pressure (PP), carotid intima-media thickness (cIMT) and carotid atherosclerosis.. This study has a cross-sectional design and includes 4924 individuals (mean age 58 years, 40% men) from Malmö, Sweden, examined between 1991 and 1994. Participants underwent physical examination, measurement of MR-proADM and ultrasound of the carotid arteries.. There was a positive association between MR-proADM and brachial PP, cIMT as well as a carotid plaque score. The associations were significant after adjustment for age, sex, BMI, hypertension, diabetes, low-density lipoprotein cholesterol and smoking.. ADM is positively associated with brachial PP and both carotid IMT and plaques, suggesting a role for ADM in early haemodynamic pathophysiology related to arteriosclerosis and the atherosclerotic plaque development.

Topics: Adrenomedullin; Arteriosclerosis; Blood Pressure; Brachial Artery; Carotid Artery Diseases; Carotid Intima-Media Thickness; Cholesterol, LDL; Cohort Studies; Cross-Sectional Studies; Female; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Peptides; Risk Factors; Sex Factors; Smoking

Revealing the mechanisms underlying the functional integrity of the vascular system could make available novel therapeutic approaches. We previously showed that knocking out the widely expressed peptide adrenomedullin (AM) or receptor activity-modifying protein 2 (RAMP2), an AM-receptor accessory protein, causes vascular abnormalities and is embryonically lethal. Our aim was to investigate the function of the vascular AM-RAMP2 system directly.. We generated endothelial cell-specific RAMP2 and AM knockout mice (E-RAMP2(-/-) and E-AM(-/-)). Most E-RAMP2(-/-) mice died perinatally. In surviving adults, vasculitis occurred spontaneously. With aging, E-RAMP2(-/-) mice showed severe organ fibrosis with marked oxidative stress and accelerated vascular senescence. Later, liver cirrhosis, cardiac fibrosis, and hydronephrosis developed. We next used a line of drug-inducible E-RAMP2(-/-) mice (DI-E-RAMP2(-/-)) to induce RAMP2 deletion in adults, which enabled us to analyze the initial causes of the aforementioned vascular and organ damage. Early after the induction, pronounced edema with enhanced vascular leakage occurred. In vitro analysis revealed the vascular leakage to be caused by actin disarrangement and detachment of endothelial cells. We found that the AM-RAMP2 system regulates the Rac1-GTP/RhoA-GTP ratio and cortical actin formation and that a defect in this system causes the disruption of actin formation, leading to vascular and organ damage at the chronic stage after the gene deletion.. Our findings show that the AM-RAMP2 system is a key determinant of vascular integrity and homeostasis from prenatal stages through adulthood. Furthermore, our models demonstrate how endothelial cells regulate vascular integrity and how their dysregulation leads to organ damage.

Topics: Adrenomedullin; Age Factors; Aging; Animals; Antigens, CD; Arteriosclerosis; Cadherins; Disease Models, Animal; Edema; Endothelium, Vascular; Fibrosis; Glomerulosclerosis, Focal Segmental; Homeostasis; Kidney; Leukocytes; Mice; Mice, Knockout; Oxidative Stress; Receptor Activity-Modifying Protein 2; Vasculitis

Pulse pressure (an indirect measure of arterial stiffness) is a robust predictor of cardiovascular events, but its pathophysiology remains poorly understood. To gain insight into the pathophysiology of arterial stiffness we conducted an exploratory investigation of the associations of 47 circulating biomarkers in etiologic pathways of arteriosclerosis with brachial artery pulse pressure.. Participants included 1,193 African-Americans and 1,145 non-Hispanic whites belonging to hypertensive sibships. Blood pressure (BP) was measured with a random-zero sphygmomanometer. Multivariable linear regression was employed to assess the associations of biomarkers with pulse pressure after adjustment for age, sex, conventional risk factors, mean arterial pressure, heart rate, and use of aspirin, statins, estrogens, and antihypertensives. Statistical significance was set at P ≤ 0.001 (Bonferroni correction for multiple testing).. Log N-terminal probrain natriuretic peptide (NT-proBNP) (African-Americans: β = 2.11 ± 0.52, non-Hispanic whites: β = 2.65 ± 0.55), log midregional proatrial natriuretic peptide (African-Americans: β = 4.83 ± 0.70, non-Hispanic whites: β = 3.70 ± 0.67), and log osteoprotegerin (African-Americans: β = 4.64 ± 1.02, non-Hispanic whites: β = 4.19 ± 0.99) were independently associated with pulse pressure (P < 0.001 for all) in both ethnicities. Log C-reactive protein (CRP) (β = 1.56 ± 0.35), log midregional proadrenomedullin (MR-proADM) (β = 5.53 ± 1.19) and log matrix metalloproteinase-2 (β = 3.89 ± 1.06) were associated with greater pulse pressure in African-Americans only (P ≤ 0.001 for all), whereas higher fibrinogen was associated with pulse pressure in non-Hispanic whites only (β = 0.02 ± 0.004. P < 0.001).. Our results suggest that hemodynamic stress, vascular inflammation and calcification, and matrix remodeling may have a role in the pathogenesis and/or adverse consequences of increased pulse pressure.

Topics: Adrenomedullin; Aged; Arteriosclerosis; Atrial Natriuretic Factor; Biomarkers; Black People; Blood Pressure; C-Reactive Protein; Female; Fibrinogen; Humans; Hypertension; Male; Matrix Metalloproteinase 2; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Protein Precursors; Vascular Stiffness; White People

Plasma adrenomedullin (AM) levels are elevated in various pathological states including cardiovascular and inflammatory diseases. The present study investigated whether an increased AM level is a marker of vascular complications in patients with atherosclerotic risks. In 114 patients with cardiovascular risks and/or diseases including ischemic heart disease (IHD) and peripheral arterial disease (PAD), plasma AM concentration and other inflammatory markers such as high sensitive C-reactive protein (CRP) and interleukin (IL)-6 were examined. The plasma AM level was not altered by the absence or presence of each of four major risk factors, i.e., hypertension, diabetes mellitus, hyperlipidemia, and smoking and its level was not significantly correlated with blood pressure, plasma glucose, or serum lipid levels. The patients with IHD had a significantly higher concentration of plasma AM than those without IHD. The AM level in subjects with PAD was also increased significantly compared with those without PAD. The plasma AM was strongly correlated with inflammatory parameters such as CRP and IL-6. Among AM, CRP, and IL-6, however, only AM was an independent predictor for both IHD and PAD by multiple logistic regression analysis. Our findings suggest the possibility that plasma AM is a novel sensitive marker for the presence of vascular lesions in patients with atherosclerotic risks.

Topics: Adrenomedullin; Arterial Occlusive Diseases; Arteriosclerosis; Biomarkers; Coronary Disease; Female; Humans; Male; Peptides; Predictive Value of Tests; Risk Factors; Sensitivity and Specificity

Arterial stiffness as measured by pulse wave velocity (PWV) is a major predictor of cardiovascular disease. Adrenomedullin (AM), a hypotensive peptide, works as a compensatory factor for arterial sclerosis. The aim of this study was to investigate the relationship between PWV and the plasma concentration of AM in risk-loading patients. One hundred and twenty-six inpatients aged 30 to 75 years with or without varying degrees of atherosclerosis were investigated. Patients with heart and/or renal failure were excluded. The PWV was measured using an automatic waveform analyzer, and the plasma AM level was measured using a newly developed, hypersensitive immunoenzymometric assay system. The PWV increased with the increasing number of cardiovascular risk factors and organ damage in the patients. A positive correlation between the PWV and AM level was observed (r=0.375, p<0.0001, n=126). Seventy-four patients were receiving antihypertensive medications; medication did not affect the correlation. Multivariate regression analysis revealed that the PWV was significantly and independently associated with age, systolic blood pressure, and AM level. These results indicate that the plasma AM concentration could serve as a marker of advanced arterial sclerosis as estimated by increased PWV.

Topics: Adrenomedullin; Adult; Aged; Arteriosclerosis; Biomarkers; Female; Heart Rate; Humans; Immunoenzyme Techniques; Male; Middle Aged; Peptides; Pulse; Risk Factors

The aim of the present study was to investigate the effect of adrenomedullin (ADM) on vascular calcification.. The vascular calcification model was established in rats (VND group) by using vitamin D3 (300,000 IU/kg) and nicotine (25 mg/kg, two doses). The effect of liposome-encapsulated ADM was observed. Vascular calcium content, alkaline phosphatase (ALP) activity, ADM in aortic tissue and plasma, binding ability of 125I-ADM for ADM receptor on vascular plasma membrane and content of cAMP in vessels were measured.. Compared with control rats, the aortic calcium content and vascular ALP activity in rats of the VDN group was obviously increased; in addition ADM concentrations in plasma and vessels of rats in VDN group were increased. But the maximum binding sites of 125I-ADM for ADM receptor (Bmax) on vascular plasma membrane in rats of VDN group were significantly decreased compared with control rats. The affinity of 125I-ADM for the ADM receptor was reduced, as shown by the Kd value and vascular cAMP content being reduced in rats of the VDN group compared to the control group. The in vitro response of isolated vessels to ADM incubation was weakened. Administration of empty liposome had no effect on vascular calcification. But administration of ADM significantly decreased vascular calcium content and ALP activity. The Bmax of 125I-ADM for ADM receptors on vascular plasma membrane increased by 17.7% (p < 0.01), and the value of Kd decreased by 36.2% (P < 0.01) in rats treated with ADM as compared with rats of the VDN group. In addition, the vascular cAMP content and the response to ADM in isolated aorta were markedly increased.. Vascular calcification induced an alteration of the vascular ADM-ADM receptor-cAMP pathway. Treatment with exogenous ADM inhibited vascular calcification by improving the vascular ADM-ADM receptor-cAMP pathway.

Topics: Adrenomedullin; Alkaline Phosphatase; Animals; Aorta, Thoracic; Aortic Diseases; Arteriosclerosis; Calcinosis; Calcium; Culture Techniques; Cyclic AMP; Disease Models, Animal; Liposomes; Male; Myocardium; Peptides; Rats; Rats, Wistar; Receptors, Adrenomedullin; Receptors, Peptide

Adrenomedullin (AM), a potent vasodilator peptide, has natriuretic effects, and its plasma concentration is elevated in cardiovascular diseases. In the present study, we investigated the induction of AM expression due to interactions between THP-1 cells (human monocytic cell line) and human umbilical cord vein endothelial cells (HUVECs). AM levels in the culture medium were measured by radioimmunoassay. The luciferase vector containing the 5'-flanking region of the human AM gene was transfected into either HUVECs or THP-1 cells. Addition of THP-1 cells to HUVECs for 48 h induced marked increases in AM levels, which were 16-fold higher than those of HUVECs alone. Luciferase vectors containing the 5'-flanking region of human AM gene (pLCF-1534) were transferred into THP-1 cells or HUVECs. Addition of THP-1 cells to pLCF-1534-transfected HUVECs induced an increase in luciferase activity in cell lysates, which was 5-fold higher than that of the transfected HUVECs alone. In contrast, the luciferase activity of lysates from pLCF-1534-transfected THP-1 cells was not affected by coculture with HUVECs. A separate coculture experiment revealed that direct contact of THP-1 cells and HUVECs contributed to enhanced AM production in the cocoulture. Co-incubation of the cell membrane fraction from THP-1 cells augmented AM production by HUVECs. Both anti-interleukin (IL)-1alpha antibody and IL-1 receptor antagonist significantly inhibited AM production in the cocultures. The cell-to-cell interaction between monocytes and HUVECs induces AM production by HUVECs, which may play an important role in the pathogenesis of vascular disorders.

Topics: Adrenomedullin; Animals; Antibodies, Monoclonal; Antigens, Surface; Arteriosclerosis; Cell Adhesion; Cell Communication; Cell Membrane; Cells, Cultured; Coculture Techniques; Endothelium, Vascular; Gene Expression Regulation; Genes, Reporter; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Leukemia, Monocytic, Acute; Luciferases; Mice; Monocytes; Peptides; Recombinant Fusion Proteins; Sialoglycoproteins; Transfection; Tumor Cells, Cultured; Vasodilation

Adrenomedullin (AM) has been implicated as having hypotensive as well as protective effects on organs and vessels against different kinds of injuries. To elucidate the in vivo pathophysiological roles of adrenomedullin, we established transgenic mice (AMTg) overexpressing adrenomedullin driven by preproendothelin-1 promoter and adrenomedullin knockout mice (AMKO). Blood pressure in AMTg was significantly lower than that in wild-type mice, and AMTg was significantly resistant to lipopolysaccharide-induced septic shock and vascular injuries. On the other hand, heterozygotes of AMKO, AM(+/-), were fully viable and hypertensive as compared with wild littermates. Mice homozygous for adrenomedullin null mutation (AM-/-) were embryonic lethal, and no embryos could survive beyond the midterm of gestation. Collectively, our findings indicate the indispensable role of adrenomedullin in circulatory homeostasis and the organ protection as well as the fetal morphogenesis and the maintenance of pregnancy.

Topics: Adrenomedullin; Animals; Arteriosclerosis; Genetic Engineering; Mice; Mice, Transgenic; Peptides

Excess oxidative stress is one of the major metabolic abnormalities on vascular walls in hypertension and atherosclerosis. In order to further elucidate the endothelial function under oxidative stress, the effect of hydrogen peroxide (H2O2) on expression of two novel endothelium-derived vasorelaxing peptides, C-type natriuretic peptide (CNP) and adrenomedullin (AM) from bovine carotid artery endothelial cells (BCAECs) was examined.. BCAECs were treated with H2O2 (0.1-1.0 mmol/ l) and/or an antioxidant, N-acetylcysteine (NAC) (5-10 mmol/l), and incubated for 48 h. The concentrations of CNP and AM were measured with the specific radioimmuno assays that we originally developed. CNP and AM mRNA expressions were also examined by reverse transcription-polymerase chain reaction (RT-PCR).. Treatment of BCAECs with 0.5 and 1 mmol/l H2O2 induced 9-and 10-fold increases of CNP concentration in the media. Addition of 10 mmol/l NAC significantly suppressed the effect of H2O2 by 52%. RT-PCR analysis showed that CNP mRNA expression in BCAECs was also rapidly augmented within 1 h with H2O2 (1 mmol/l) treatment, and reached a peak at 3 h to show a 10-fold increase. AM secretion from BCAECs also increased to two-fold with exposure to 0.5 mmol/l H2O2, accompanied with the augmented level of AM mRNA. NAC 10 mmol/l completely suppressed the effect of H2O2 on AM secretion.. In this study, it has been demonstrated that H2O2 augments endothelial secretion of the two endothelium-derived relaxing peptides, CNP and AM. Our findings suggest the increased secretion of CNP and AM from endothelium under oxidative stress may function to compensate the impaired nitric oxide-dependent vasorelaxation in hypertension and atherosclerosis.

Topics: Acetylcysteine; Adrenomedullin; Animals; Antioxidants; Arteriosclerosis; Base Sequence; Cattle; Cells, Cultured; DNA Primers; Endothelium, Vascular; Gene Expression; Humans; Hydrogen Peroxide; Hypertension; Natriuretic Peptide, C-Type; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Oxidative Stress; Peptides; RNA, Messenger; Vasodilation

Macrophages secrete a variety of growth factors, cytokines and vasoactive peptides, which are related to the progression of atherosclerosis. Adrenomedullin (ADM) is a potent vasodilator peptide and inhibits proliferation and migration of vascular smooth muscle cells. In this study, we investigated the production and secretion of ADM by monocytes and macrophages by Northern blot analysis, RIA and immunocytochemistry. Northern blot analysis showed that ADM mRNA was expressed in human monocytes obtained from peripheral blood and monocyte-derived macrophages. The expression level of ADM mRNA in monocyte-derived macrophages was about five times higher than that in monocytes. Treatment with lipopolysaccharide (100 ng/ml) for 24 h increased ADM mRNA expression levels in both monocytes and monocyte-derived macrophages. The levels of immunoreactive ADM in the media of monocyte-derived macrophages were about three times higher than that of monocytes (0. 718+/-0.046 fmol/24 h/10(5) cells, n=8 compared with 0.259+/-0.018 fmol/24 h/10(5) cells, n=8; mean+/-S.E.M., P<0.01). The secretion was also increased by treatment with lipopolysaccharide. Immunocytochemistry showed positive ADM immunostaining in macrophages in atherosclerotic lesions of human aorta obtained at autopsy. ADM secreted from activated macrophages may play an inhibitory role in atherogenesis.

Topics: Adrenomedullin; Aged; Aged, 80 and over; Aortic Diseases; Arteriosclerosis; Blotting, Northern; Cell Culture Techniques; Chromatography, High Pressure Liquid; Female; Humans; Immunoenzyme Techniques; Macrophages; Male; Middle Aged; Monocytes; Peptides