Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Adrenomedullin in monocytes and macrophages: possible involvement of macrophage-derived adrenomedullin in atherogenesis. 1040 81

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.
Atherosclerosis 2001 Apr
PMID:Interaction between monocytes and vascular endothelial cells induces adrenomedullin production. 1125 8

Adrenomedullin and endothelin are novel peptides that are produced in the blood vessel wall and have contrasting biologic actions. Both may play a pathophysiological role in atherosclerosis and chronic heart failure. It has also been suggested that both peptides may be metabolized by neutral endopeptidase and that pharmacological manipulation of this enzyme may be of therapeutic interest. We investigated the effect of thiorphan, a neutral endopeptidase inhibitor, on the vasodilator response to adrenomedullin and the vasoconstrictor response to endothelin in small resistance arteries taken from patients with heart failure caused by coronary heart disease. Small resistance arteries were dissected from gluteal biopsy samples and studied with wire myography. Thiorphan did not affect the vasodilator response to adrenomedullin in arteries preconstricted with norepinephrine. Maximal responses were 66% (SD 11%) and 72% (8%) in the absence and presence of thiorphan, respectively (n=8). The vasoconstrictor response to endothelin was also unaffected. The maximum vasoconstrictor responses in the absence and presence of thiorphan were 152% (11%) and 132% (12%), respectively (n=8). The values of corresponding -log concentrations of agonist required to effect a 50% response (pD(2)) were 8.52 (0.11) and 8.64 (0.15), respectively. We showed that the inhibition of neutral endopeptidase does not augment the vasodilator and vasoconstrictor activities of adrenomedullin and endothelin, respectively, in small resistance arteries from patients with chronic heart failure. This suggests that neutral endopeptidase inhibition, as a therapeutic strategy, will enhance neither the potentially desirable vascular actions of adrenomedullin nor the potentially unfavorable vascular effects of endothelin-1 in human cardiovascular disease states.
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PMID:Effect of neutral endopeptidase inhibition on the actions of adrenomedullin and endothelin-1 in resistance arteries from patients with chronic heart failure. 1156 14

Adrenomedullin is known to inhibit cell proliferation in cultured rat vascular smooth muscle cells, through a cAMP-dependent process. The calcitonin receptor-like receptor could function as an adrenomedullin receptor when co-expressed with receptor activity-modifying protein 2. To determine whether vascular adrenomedullin receptor components, the calcitonin receptor-like receptor and the receptor activity-modifying protein 2, phenotypically change during in vitro culture conditions, we examined the expression of adrenomedullin receptor components, adrenomedullin-induced cAMP production, and the inhibition of cell proliferation in culture rat vascular smooth muscle cells during serial passages. The results demonstrated that the receptor activity-modifying protein 2 and calcitonin receptor-like receptor mRNAs increased in a passage-dependent manner in rat vascular smooth muscle cells. Furthermore, the responses of both the elevation of cAMP and the inhibition of cell proliferation became larger in vascular smooth muscle cells with an increasing number of passages. The results suggest that the increase in functional AM receptor during phenotypic change may in part contribute to the development of vascular lesions, such as in atherosclerosis.
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PMID:Phenotypic changes of adrenomedullin receptor components, RAMP2, and CRLR mRNA expression in cultured rat vascular smooth muscle cells. 1167 73

Adrenomedullin is a potent vasodilator peptide exerting anti-atherosclerotic actions in vitro. We investigated the impact of the severity of atherosclerosis on plasma mature-adrenomedullin (m-AM) levels in 38 patients with chronic ischemic stroke. The variables of carotid artery atherosclerosis assessed using ultrasound measurement, blood pressure, and risk factors were related to m-AM levels. Severe atherosclerosis was associated with a further elevation of the increased m-AM level in patients with high systolic blood pressure. Even in patients with fewer risk factors, the presence of severe atherosclerosis was associated with an increased m-AM level. Thus, atherosclerosis elevates m-AM independent of the blood pressure level or presence of risk factors.
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PMID:Association of plasma adrenomedullin with carotid atherosclerosis in chronic ischemic stroke. 1175 75

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.
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PMID:Plasma adrenomedullin is closely correlated with pulse wave velocity in middle-aged and elderly patients. 1471 80

Adrenomedullin (AM), a potent vasodepressor, is known to have anti-atherosclerotic and anti-inflammatory effects. However, there is no information about its level in severe atherosclerotic diseases, such as peripheral arterial occlusive disease (PAOD). The present study investigated the plasma concentration of AM and several inflammatory parameters in 72 patients with and without PAOD. The plasma AM concentration in patients with PAOD was significantly higher than in those without PAOD. Its concentration had significant correlations with ankle-brachial index and Fontaine's stage. The plasma AM level also correlated with high sensitive C-reactive protein and interleukin-6. As an additional study, plasma levels of two forms of AM drawn from the femoral artery and saphenous vein were measured in 27 other subjects. Both mature and intermediate forms of plasma AM in the femoral artery and saphenous vein were higher in patients with PAOD than in those without PAOD. A significant step-up of the mature form of AM from the femoral artery to the saphenous vein was observed. Our findings indicate that the plasma AM concentration was elevated in patients with PAOD in proportion to the severity of the disease and associated with vascular inflammation. An increased production of AM in PAOD may play a protective role against advanced atherosclerosis with an inflammatory signature.
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PMID:Plasma adrenomedullin concentration is increased in patients with peripheral arterial occlusive disease associated with vascular inflammation. 1475 62

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.
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PMID:Adrenomedullin: a protective factor for blood vessels. 1614 6

Adrenomedullin (ADM) is a vasoactive peptide found to be related to obesity and its comorbidities: type 2 diabetes, hypertension, atherosclerosis, and coronary heart disease. ADM is increased both in plasma and in adipose tissue of obese individuals when compared to lean subjects and is considered as a member of the adipokine family. We determined plasma midregional proadrenomedullin (MR-proADM) concentrations in a cohort of 357 subjects with BMI ranging from 17.5 to 42.3 kg/m2 and no additional medical history. In parallel, 28 severely obese patients scheduled to undergo laparoscopic Roux-en-Y gastric bypass (RYGB) surgery were studied at two time points: before and 1 year after surgery. Outcome measurements were: MR-proADM, cortisol, leptin, C-reactive protein (CRP) thyroid-stimulating hormone (TSH), creatinine and metabolic parameters. BMI correlated significantly to plasma MR-proADM levels (r=0.714, P<0.001), also after adjustment for age and gender (r=0.767, P<0.001). In obese subjects, there was a positive relationship between MR-proADM and leptin (r=0.511, P=0.006). Following RYGB, plasma MR-proADM decreased from 0.76+/-0.03 to 0.62+/-0.02 pg/ml (P<0.0001). RYGB-induced changes in MR-proADM correlated significantly to changes in leptin (r=0.533, P=0.004) and in CRP (r=0.429, P=0.023). We conclude that BMI is an independent predictor of circulating MR-proADM levels. Weight loss after RYGB is associated with a significant decrease in plasma MR-proADM, which is related to surgery-induced changes in both circulating leptin and systemic inflammation.
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PMID:Plasma MR-proADM correlates to BMI and decreases in relation to leptin after gastric bypass surgery. 1924 78

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.
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PMID:Adrenomedullin ameliorates the development of atherosclerosis in apoE-/- mice. 2033 6


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