Adrenomedullin Stimulates Two Signal Transduction Pathways, cAMP Accumulation and Ca2+ Mobilization, in Bovine Aortic Endothelial Cells

Shimekake, Yoshiyuki; Nagata, Kiyoshi; Ohta, Shigeki; Kambayashi, Yoshikazu; Teraoka, Hiroshi; Kïtamura, Kazuo; Eto, Tanenao; Kangawa, Kenji; Matsuo, Hisayuki

doi:10.1074/jbc.270.9.4412

Cited by 345 publications

(221 citation statements)

References 31 publications

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“…It must be mentioned however, in contradiction to the theory that ADM inhibits aldosterone secretion, that ADM itself stimulates two signal transduction pathways; cAMP accumulation and Ca 2+ mobilisation (Shimekake et al 1995). Both these second messenger mechanisms are utilised by various factors, such as ACTH, to stimulate aldosterone secretion.…”

Section: Discussionmentioning

confidence: 76%

Effect of adrenomedullin infusion on basal and stimulated aldosterone secretion in conscious sheep with cervical adrenal autotransplants

Salemi

McDougall²,

Hardy³

et al. 2000

Journal of Endocrinology

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In vivo and in vitro studies have shown conflicting effects of adrenomedullin (ADM) on the secretion of steroid hormones from the adrenal gland. While some investigators report no effect of this peptide on the output of various hormones, others have reported both stimulatory and inhibitory roles for ADM. We have shown that basal aldosterone secretion rate (ASR), in conscious sheep with cervical adrenal autotransplants, did not change when ADM was infused directly into the adrenal arterial supply. While not affecting basal ASR, ADM did produce pronounced increases in adrenal blood flow (BF). This elevation of BF in association with ADM infusion was seen in all subsequent experiments. When aldosterone output was acutely stimulated by angiotensin II (AngII), potassium chloride (KCl) and adrenocorticotrophic hormone (ACTH), ADM was seen to drastically reduce the secretion of aldosterone with all agonists studied. After pre-exposure to ADM, all three agonists increased ASR but the magnitude of the responses were somewhat blunted. ADM did not have the same effect on cortisol secretion stimulated by ACTH, suggesting that the ability of this peptide to influence adrenal gland function is limited to the zona glomerulosa. In conditions of chronic elevation of aldosterone levels, such as in Na deficiency, ADM did not display the same inhibitory abilities seen in the acute stimulation experiments. Hence, ADM has been shown to have a direct, inhibitory role on the acute stimulation of aldosterone by AngII, KCl and ACTH while not affecting basal or chronic aldosterone secretion or cortisol secretion stimulated by ACTH.

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Section: Discussionmentioning

confidence: 76%

Effect of adrenomedullin infusion on basal and stimulated aldosterone secretion in conscious sheep with cervical adrenal autotransplants

Salemi

McDougall²,

Hardy³

et al. 2000

Journal of Endocrinology

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“…[2][3][4] AM not only induces vasorelaxation but also regulates growth and death of these vascular cells. [5][6][7][8][9][10] These findings suggest that AM plays an important role in maintaining vascular homeostasis in an autocrine and/or paracrine manner.…”

mentioning

confidence: 77%

Adrenomedullin Gene Transfer Induces Therapeutic Angiogenesis in a Rabbit Model of Chronic Hind Limb Ischemia

et al. 2004

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Background— Earlier studies have shown that adrenomedullin (AM), a potent vasodilator peptide, has a variety of cardiovascular effects. However, whether AM has angiogenic potential remains unknown. This study investigated whether AM gene transfer induces therapeutic angiogenesis in chronic hind limb ischemia. Methods and Results— Ischemia was induced in the hind limb of 21 Japanese White rabbits. Positively charged biodegradable gelatin was used to produce ionically linked DNA-gelatin complexes that could delay DNA degradation. Human AM DNA (naked AM group), AM DNA-gelatin complex (AM-gelatin group), or gelatin alone (control group) was injected into the ischemic thigh muscles. Four weeks after gene transfer, significant improvements in collateral formation and hind limb perfusion were observed in the naked AM group and AM-gelatin group compared with the control group (calf blood pressure ratio: 0.60±0.02, 0.72±0.03, 0.42±0.06, respectively). Interestingly, hind limb perfusion and capillary density of ischemic muscles were highest in the AM-gelatin group, which revealed the highest content of AM in the muscles among the three groups. As a result, necrosis of lower hind limb and thigh muscles was minimal in the AM-gelatin group. Conclusions— AM gene transfer induced therapeutic angiogenesis in a rabbit model of chronic hind limb ischemia. Furthermore, the use of biodegradable gelatin as a nonviral vector augmented AM expression and thereby enhanced the therapeutic effects of AM gene transfer. Thus, gelatin-mediated AM gene transfer may be a new therapeutic strategy for the treatment of peripheral vascular diseases.

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“…Consistent with this, in cultured vascular endothelial cells, AM was found to stimulate phospholipase C activation and inositol 1,4,5-triphosphate formation, resulting in an elevation of the intracellular Ca 2ϩ level and activation of NO synthase. 65 Kato et al reported that AM inhibited serum deprivation-induced apoptosis of cultured rat vascular endothelial cells. 61 Blockade of the endogenous AM by anti-AM anti-serum impaired the inhibitory effect of the nonimmune serum on apoptosis, suggesting an autocrine or paracrine role for AM.…”

Section: Vascular Protective Effects In Vitromentioning

confidence: 99%

Adrenomedullin

Kato

Tsuruda

Kita

et al. 2005

ATVB

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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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Adrenomedullin Stimulates Two Signal Transduction Pathways, cAMP Accumulation and Ca2+ Mobilization, in Bovine Aortic Endothelial Cells

Cited by 345 publications

References 31 publications

Effect of adrenomedullin infusion on basal and stimulated aldosterone secretion in conscious sheep with cervical adrenal autotransplants

Effect of adrenomedullin infusion on basal and stimulated aldosterone secretion in conscious sheep with cervical adrenal autotransplants

Adrenomedullin Gene Transfer Induces Therapeutic Angiogenesis in a Rabbit Model of Chronic Hind Limb Ischemia

Adrenomedullin

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