The studies for expression and secretion of adrenomedullin and characterzation of its receptors.

肾上腺髓质素表达和分泌及其受体表征的研究。

• 批准号: 06454344
• 负责人: KANGAWA Kenji
• 金额: $ 4.67万
• 依托单位: NATIONAL CARDIOVASCULAR CENTER RESEARCH INSTITUTE
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (B)
• 财政年份: 1994
• 资助国家: 日本
• 起止时间: 1994 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-06454344/
• 关键词: adrenomedullin (AM); vasorelaxant peptide; cardiovascular disease; cAMP; cytokine; endotoxin shock; endothelial cells (EC); vascular smooth muscle cells (VSMC); 降圧ペプチド; 発現,分泌調節機序; 培養血管内皮細胞(EC); 培養血管び平滑筋細胞(VSMC); 循環ホルモン; 局所因子; 受容体解析

Adrenomedullin (AM) is a potent vasorelaxant peptide recently isolated from human pheochromocytoma tissue, and is structurally a member of CGRP family. mRNA of AM is highly expressed in several tissues including heart, lung and kidney as well as adrenal medulla. In this project, we have studied the expression and secretion of AM and characterization of its receptors.The radioimmunoassay established for adrenomedullin has demonstrated that AM is circulating in blood and the plasma levels of AM in the patients of cardiovascular diseases are higher than those of healthy controls. We have found that cultured endothelial cells (EC) and vascular smooth muscle cells (VSMC) actively produce AM.Gene expression levels of AM in rat EC and VSMC were far higher than that in adrenal gland, and a significant levels of AMm RNA was detected in intact aorta.Tumor necrosis factor (TNF), interleukin-1 (IL-1) and lipopolysaccharide (LPS), major factors inducing endotoxin shock, were shown to most potently … More stimulate production and gene transcription of AM both in VSMC and in EC.LPS injection into rat (5mg/kg) markedly increased plasma AM concentration (20 times of control), and positive AM gene transcription was observed in all the examined tissue of LPS-injected rat. These data indicate the possible paricipation of AM as a vasodilator in the blood pressure regulation in the endotoxin shock.The receptors for AM in VSMC and EC have been characterized. AM and CGRP increased intracellular cAMP throuh their receptors both in VSMC and in EC.Both AM and CGRP-induced elevations of the cAMP in VSMC were abolished in the presence of CGRP-(8-37), a CGRP receptor antagonist. CGRP-(8-37) also inhibited the cAMP accumulation in EC by CGRP,but had no effect on that by AM.These findings indicate that at least two types of receptor for AM may be present, and one is specific for AM and the other is shared with AM and CGRP.The studies of action mechanism of AM suggest that NO pathway as well as cAMP pathway may be involved in the regulation of cardiovascular system by AM.The present study indicates the presence of a local regulatory system of vascular tone by AM in the blood vessel. Less

肾上腺髓质素(AM)是新近从人嗜铬细胞瘤组织中分离得到的一种有效的血管舒张肽，结构上属于CGRP家族成员。AM的mRNA在心、肺、肾和肾上腺髓质等组织中高表达。本课题对AM的表达、分泌及其受体的特性进行了研究，建立的肾上腺髓质素放射免疫分析方法表明，AM在血液中循环，心血管疾病患者血浆AM水平高于健康对照组。我们发现，培养的血管内皮细胞和血管平滑肌细胞能主动产生AM。大鼠内皮细胞和血管平滑肌细胞AM的基因表达水平远远高于肾上腺，在完整的主动脉中检测到显著的AMM RNA水平。引起内毒素休克的主要因素肿瘤坏死因子、白细胞介素1和内毒素对…的作用最强内毒素(5 mg/kg)对VSMC和EC.AM的产生和基因转录均有较强的刺激作用，可使血浆AM浓度显著升高(是对照组的20倍)，且在所有组织中均可见AM基因转录阳性。这些数据表明AM可能作为血管扩张剂参与内毒素休克时的血压调节。AM和CGRP均通过其受体使VSMC和EC内cAMP升高。CGRP受体拮抗剂CGRP-(8-37)可阻断AM和CGRP引起的VSMC内cAMP升高。CGRP-(8-37)也可抑制CGRP诱导的EC内cAMP积聚，但对AM的cAMP积聚无影响。上述结果表明，AM至少存在两种受体，一种是AM所特有的，另一种是AM和CGRP所共有的。对AM作用机制的研究表明，AM对心血管系统的调节可能与cAMP途径无关。较少

项目成果

Shimekake Y., et al.: "Adrenomedullin stimulates two signal transduction pathways, cAMP accumulation and Ca^<2+> Mobilization. in bovine aortic endothelial cells." J. Biol. Chem.270. 4412-4417 (1995)

Shimekake Y.等人：“肾上腺髓质素刺激牛主动脉内皮细胞中的两种信号转导途径，即cAMP积累和Ca 2+ 动员。”

藤田敏郎 編(分担)寒川賢治 他: "メディカル用語ライブラリー 高血圧(分担)アドレノメデュリンとPAMP" 羊土社, 211 (1995)

藤田敏郎（合著者）寒川健二等主编：《医学术语图书馆高血压（合著者）肾上腺髓质素和 PAMP》《Yodosha》，211（1995 年）

K.Kitamura, K.Kangawa, H.Matsuo, T.Eto: "Adrenomedullin : Implication for hypertension research." Drugs. 49. 485-495 (1995)

K.Kitamura、K.Kangawa、H.Matsuo、T.Eto：“肾上腺髓质素：对高血压研究的启示。”

Shimekake Y., et al.: "Adrenomedullin stimukates two signal transduction pathways, cAMP accumulation and Ca^<2+> Mobilization, in bovine aortic endothelial cells." J. Biol. Chem.270. 4412-4417 (1995)

Shimekake Y.等人：“肾上腺髓质素刺激牛主动脉内皮细胞中的两种信号转导途径，即cAMP积累和Ca 2+ 动员。”

K.Nakamura, H.Toda, K.Terasako, M.Kakuyama, Y.Hatano, K.Mori, K.Kangawa: "Vasodilative effect of adrenomedullin in isolated arteries of the dog." Jpn.J.Pharmacol.67. 259-262 (1995)

K.Nakamura、H.Toda、K.Terasako、M.Kakuyama、Y.Hatano、K.Mori、K.Kangawa：“肾上腺髓质素对狗离体动脉的血管舒张作用。”