Adrenomedullin as a Novel Antimigration Factor of Vascular Smooth Muscle Cells

Horio, Takeshi; Kohno, Masakazu; Kano, Hiroaki; Ikeda, Motohisa; Yasunari, Kenichi; Yokokawa, Koji; Minami, Mieko; Takeda, Tadanao

doi:10.1161/01.res.77.4.660

Cited by 137 publications

(76 citation statements)

References 36 publications

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“…69 Horio et al reported an inhibitory effect of AM on the migration of cultured SMCs, which is presumably mediated by intracellular cAMP. 70 Inhibition of the migration of SMCs by AM was confirmed by an independent group, 34 but according to this report, AM inhibited migration via a cAMP-independent mechanism. 34 These discrepancies may have resulted from differences in the experimental conditions or types of cultured cells used, though there has currently been no clear explanation.…”

Section: Vascular Protective Effects In Vitromentioning

confidence: 51%

Adrenomedullin

Kato

Tsuruda

Kita

et al. 2005

ATVB

145

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Abstract-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. Key Words: adrenomedullin Ⅲ vasodilatation Ⅲ endothelium Ⅲ smooth muscle cell Ⅲ arteriosclerosis C ardiovascular diseases secondary to arteriosclerosis of blood vessels are currently among the leading causes of death in developed countries. A number of factors, both humoral and mechanical, have been shown to modulate vascular function in humans as well as in experimental animals. 1 Blood vessel dysfunction resulting from an imbalance of those factors accelerates the process of vascular remodeling and atherosclerosis. 1 Vasoconstrictors including angiotensin II and endothelins not always but mostly act as proatherogenic factors, whereas vasodilators, either peptides or non-peptides, such as natriuretic peptides, nitric oxide (NO), and prostaglandin (PG) I 2 , have antiatherogenic properties. 1 In 1993, a new vasodilator peptide, adrenomedullin (AM), was isolated from the tissue extract of a human pheochromocytoma by monitoring cAMP levels in rat platelets. 2 Substantial levels of the AM peptide and gene expression were detected in the cardiovascular tissues including blood vessels. As listed in the Table, AM was found to exert a wide range of biological actions related to vascular functions in cultured cells, with which observations in vivo have been mostly accordant. Ever since the discovery of AM, efforts have been made to clarify the role of this bioactive peptide in blood vessels and a substantial amount of basic and clinical data has been accumulated. In this review, after summarizing the biochemical and pharmacological features of AM, we discuss its role in blood vessels, which is assumed to be protective, or inhibitory against the progression of vascular damage and remodeling. Biochemistry of AMHuman AM is a 52-aa peptide with a ring structure formed by a disulfide bond and amidated tyrosine at the C terminus ( Figure 1), both essential for binding to receptors and biological activity. 2-4 Based on sequence homology, AM is thought to belong to the calcitonin gene-related peptide (CGRP) superfamily. [2][3][4] Cloning of the cDNA encoding AM revealed the AM precursor peptide preproAM to comprise 185 amino acids, with the C terminus followed by a pair of basic amino acids, Arg-Arg, a typical processing signal (...

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Section: Vascular Protective Effects In Vitromentioning

confidence: 51%

Adrenomedullin

Kato

Tsuruda

Kita

et al. 2005

ATVB

145

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“…For example, the cAMP activator forskolin as well as stable cAMP analogues such as 8-bromo-cAMP are effective inducers of PKA activity and inhibitors of smooth muscle cell migration (17,19). In addition, adrenomedullin has also been shown to inhibit the migration of rat aortic smooth muscle cells by inducing intracellular cAMP accumulation (17).…”

Section: Discussionmentioning

confidence: 99%

“…These results indicated that apoE inhibition of fibroblast migration is also mediated via induction of cAMP accumulation and the consequential activation of PKA. Finally, to verify that the lack of apoE-induced cAMP accumulation in LRP-deficient cells is not a generalized phenomenon of abnormal cyclic nucleotide metabolism due to LRP-1 deficiency, we tested the effect of forskolin, a direct activator of adenylyl cyclase and inhibitor of smooth muscle cell migration (17,19), on the migration of MEF-1, PEA-10, and PEA-13 cells. Results, as shown in Fig.…”

Section: Apoe Induced Camp Accumulation Via Its Interaction With Lrp-mentioning

confidence: 99%

Apolipoprotein E Binding to Low Density Lipoprotein Receptor-related Protein-1 Inhibits Cell Migration via Activation of cAMP-dependent Protein Kinase A

Zhu

Hui

2003

Journal of Biological Chemistry

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Smooth muscle cell migration and proliferation contribute to neointimal hyperplasia and vascular stenosis after endothelial denudation. Previous studies revealed that apolipoprotein E (apoE) is an effective inhibitor of platelet-derived growth factor-directed smooth muscle cell migration and proliferation and that the anti-migratory function is mediated via apoE binding to low density lipoprotein receptor-related protein-1 (LRP-1). This study was undertaken to identify the intracellular pathway by which apoE binding to LRP-1 results in inhibition of smooth muscle cell migration. The results showed that apoE increased intracellular cAMP levels 3-fold after 5 min, and the increase was sustained for more than 1 h. As a consequence, apoE also increased protein kinase A (PKA) activity in smooth muscle cells. Importantly, suppression of PKA activity with a cellpermeable peptide inhibitor of PKA abolished the inhibitory effect of apoE on smooth muscle cell migration. These results indicated that apoE inhibition of smooth muscle cell migration is mediated via the activation of cAMP-dependent PKA. Additional experiments revealed that apoE also inhibited fibroblasts migration toward platelet-derived growth factor by a similar mechanism of cAMP-dependent PKA activation. It is noteworthy that apoE failed to increase cAMP levels or inhibit migration of LRP-1-negative mouse embryonic fibroblasts and LRP-1-deficient smooth muscle cells. Taken together, these findings established the mechanism by which apoE inhibits cell migration, i.e. via cAMP-dependent protein kinase A activation as a consequence of its binding to LRP-1.The importance of apolipoprotein E (apoE) 1 in protecting against atherosclerosis was convincingly demonstrated by studies with experimental animals. Transgenic mice overexpressing rat apoE displayed marked resistance to diet-induced hypercholesterolemia and did not develop atherosclerosis (1, 2). In contrast, mice with targeted disruption of the apoE gene developed spontaneous atherosclerosis even under basal low fat/low cholesterol dietary conditions (3, 4). Atherosclerosis in apoE-null mice could be prevented by increasing circulating apoE levels through recombinant adenovirus-mediated apoE gene transfer to the liver (5). The decrease in atherosclerosis in this model was accompanied by decreased total cholesterol, very low density lipoprotein, and intermediate density lipoprotein levels (5). Although these results seemed to suggest that apoE prevents atherosclerosis by lowering plasma cholesterol levels, atherosclerosis was found to be more severe in cholesterol-fed apoE ϩ/Ϫ mice than in cholesterol-fed apoE ϩ/ϩ mice despite the relative similar plasma cholesterol level in the two groups (4, 6). Additionally, transgenic expression of apoE in the arterial wall inhibited atheroma formation and severity without affecting plasma cholesterol level in cholesterol-fed C57BL/6 mice (1). Subsequent studies showed that low levels of apoE secreted by the adrenal gland also inhibited atherosclerosis without correcting...

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“…Recent studies clarified that adrenomedullin is synthesized in various tissues, including vascular smooth muscles, glomerular mesangium, cardiac tissues and lungs [2,3,16]. Adrenomedullin has vasodilator and antiproliferative effects in vascular smooth muscle cells and mesangial cells [2,7]. These effects are obtained as a paracrine or autocrine mechanism [8,17,18].…”

Section: Hormonal Assaysmentioning

confidence: 99%

“…Previous studies reported that the plasma concentration of adrenomedullin increases in patients with hypertension, renal failure and congestive heart failure [4,5], though the major source of circulating adrenomedullin is unknown. Adrenomedullin has vasodilator and antiproliferative actions in vascular smooth muscle and glomerular mesangium [6,7], as a paracrine or autocrine mechanism [8]. Diabetes mellitus has chronic complications, including retinopathy, neuropathy and nephropathy, which are closely related to microangiopathy [9,10].…”

mentioning

confidence: 99%

Plasma Adrenomedullin Levels in Patients with Non-Insulin Dependent Diabetes Mellitus: Close Relationships with Diabetic Complications.

Nakamura¹,

Honda²,

Ishikawa³

et al. 1998

Endocr J

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Abstract.The present study was undertaken to determine plasma adrenomedullin levels in patients with non-insulin dependent diabetes mellitus (NIDDM) to elucidate the potential involvement in the pathogenesis of diabetic complications. The patients were 24 males and 21 females with ages of 55 ± 2.1 years (mean ± SEM). Plasma adrenomedullin levels were 5.94 ± 0.44 pmol/l in patients with NIDDM, and were not affected by plasma glucose concentration.

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Adrenomedullin as a Novel Antimigration Factor of Vascular Smooth Muscle Cells

Cited by 137 publications

References 36 publications

Adrenomedullin

Adrenomedullin

Apolipoprotein E Binding to Low Density Lipoprotein Receptor-related Protein-1 Inhibits Cell Migration via Activation of cAMP-dependent Protein Kinase A

Plasma Adrenomedullin Levels in Patients with Non-Insulin Dependent Diabetes Mellitus: Close Relationships with Diabetic Complications.

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