2002 Fiscal Year Final Research Report Summary
Molecular Mechanism for the Adrenomedullin Actions in the Cardiovascular Tissue
| Project/Area Number |
12470159
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Miyazaki Medical College |
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Principal Investigator |
ETO Tanenao Miyazaki Medical College, 1st Dept Intern Med, Professor, 医学部, 教授 (10038854)
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| Co-Investigator(Kenkyū-buntansha) |
KITA Toshihiro Miyazaki Medical College, 1st Dept Intern Med, Research Associate, 医学部, 助手 (70315365)
KATO Johji Miyazaki Medical College, 1st Dept Intern Med, Research Associate, 医学部, 助手 (20274780)
KITAMURA Kazuo Miyazaki Medical College, 1st Dept Intern Med, Lecturer, 医学部, 講師 (50204912)
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| Project Period (FY) |
2000 – 2002
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| Keywords | adrenomedullin / locally-acting hormone / cardiac hypertrophy / cardiac remodeling / vascular remodeling / CRLR / RAMP / 圧容量負荷 |
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| Research Abstract |
Aim of this study : This research project was planned to clarify the molecular mechanisms for the actions and roles of adrenomedullin (AM) in the cardiovascular tissues. Results : (1) AM was found to act as an autocrine or paracrine factor inhibiting hypertrophy of cardiomyocytes and proliferation of cardiac fibroblasts. The inhibitory action of AM on cardiac fibroblast proliferation is mediated at least in part by cAMP. (2) Calcitonin-receptor-like receptor (CRLR) and receptor-activity-modifying proteins (RAMPs) act together to function as AM receptors. Both Ang II and ET-1 were found to modulate the gene expressions of CRLR and RAMPs altering intracellular cAMP response to AM in the cardiac myocytes. (3) Gene expressions of AM and AM receptor components in the cardiac ventricles increased in relation to the magnitude of cardiac hypertrophy in rats with aortic banding and aortocaval shunt. (4) Extracellular domains of RAMPs that is essential for receptor binding were identified, and the mutant RAMPs without these portions were found to act as dominant negative RAMPs. (5) Cultured human vascular smooth muscle cells produced AM, and the AM production was stimulated by aldosterone, a steroid hormone which causes the cardiovascular damage or remodeling. (6) The ex vivo experiments showed that the intermediate form AM-Gly dilates rat aorta following conversion to mature AM in aortic tissue. Conclusion : The present findings suggest that AM participates in cardiovascular homeostasis as a locally-acting hormone. Many of the AM actions cardiovascular tissues appear to be mediated by the CRLR-RAMP system, while other receptor system(s) and intracellular mechanisms of action remain to be elucidated.
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Research Products
(21 results)
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[Publications] Cao, Y., Kitamura, K., Ito, K., Kato, I., Hashida, S., Morishita, K., and Eta, T.: "Glycine-extended adrenomedullin exerts vasodilator effect through amidation in the rat aorta."Regul. Pept.. 2918. 1-7 (2003)
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[Publications] Nakamura, R., Kato, J., Kitamura, K., Onitsuka, H., Imamura, T., Marutsuka, K., Asada, Y., Kangawa, K., and Eto, T.: "Beneficial effects of adrenomedullin on left ventricular remodeling after myocardial infarction in rats."Cardiovasc. Res.. 56. 373-380 (2002)
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[Publications] Nagoshi, Y., Kuwasako, K., Ito, K., Uemura, T., Kato, J., Kitamura, K., and Eto, T.: "The calcitonin receptor-like receptor/receptor activity-modifying protein 1 heterodimer can function as a calcitonin gene-related peptide-(8-37)-sensitive adrenomedullin receptor."Eur. J. Pharmacol.. 450. 237-243 (2002)
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[Publications] Kuwasako, K., Kitamura, K., Onitsuka, H., Uemura, T., Nagoshi, Y., Kato, J., and Eto, T.: "Rat PAMP domains involved in adrenomedullin binding specificity."FEBS Lett.. 519. 113-116 (2002)
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[Publications] Uemura, T., Kato, J., Kuwasako, K., Kitamura, K., Kangawa, K., and Eto, T.: "Aldosterone augments adrenomedullin production without stimulating pro-adrenomedullin N-terminal 20 peptide secretion in vascular smooth muscle cells."J. Hypertens. 20. 1209-1214 (2002)
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[Publications] Yuchi, H., Suganuma, T., Sawaguchi, A., Ide, S., Kawano, J., Aoki, T., Kitamura, K., and Eto, T.: "Cryofixation processing is an excellent method to improve the retention of adrenomedullin antigenicity."Histochem. Cell. Biol.. 118. 259-265 (2002)
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[Publications] Tsuruda, T., Kato, J., Kitamura, K., Mishima, K., Imamura, T., Koiwaya, Y., Kangawa, K., and Eto, T.: "Roles of protein kinase C and Ca^<2+>-dependent signaling in angiotensin II-induced adrenomedullin production in rat cardiac myocytes."J. Hypertens.. 19. 757-763 (2001)
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[Publications] Mishima, K., Kato, J., Kuwasako, K., Ito, K., Imamura, T., Kitamura, K., and Eto, T.: "Effects of endothelin on adrenomedullin secretion and expression of adrenomedullin receptors in rat cardiomyocytes."Biochem. Biophys. Res. Commun.. 287. 264-269 (2001)
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[Publications] Tsuruda, T., Kato, J., Kitamura, K., Kuwasako, K., Imamura, T., Koiwaya, Y., Kangawa, K., and Eto, T.: "Secretion of proadrenomedullin N-terminal 20 peptide from cultured neonatal rat cardiac cells."Life Sci.. 69. 239-245 (2001)
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[Publications] Kitamura, K., Matsui, E., Kato, J., Kato, F., Kita, T., Tsuji, T., Kangawa, K., and Eto, T.: "Adrenomedullin (11-26) : a novel endogenous hypertensive peptide isolated from bovine adrenal medulla."Peptide. 22. 1713-1718 (2001)
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[Publications] Kuwasako, K., Kitamura, K., Ito, K., Uemura, T., Yanagita, Y., Kato, J., Sakata, T., and Eto, T.: "The seven ammo acids of human RAMP2 (86-92) and RAMP3 (59-65) are critical for agonist binding to human adrenomedullin receptors."J. Biol. Chem.. 276. 49459-49465 (2001)
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[Publications] Tsuruda, T., Kato, J., Kitamura, K., Imamura, T., Koiwaya, Y., Kangawa, K., Komuro, I., Yazaki, Y., and Eto, T.: "Enhanced adrenomedullin production by mechanical stretching in cultured rat cardiomyocytes."Hypertension. 35. 1210-1214 (2000)
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[Publications] Yamakawa, H., Imamura, T., Matsuo, T., Onitsuka, H., Tsumori, Y., Kato, J., Kitamura, K., Koiwaya, Y., and Eto, T.: "Diastolic wall stress and ANG II in cardiac hypertrophy and gene expression induced by volume overload."Am. J. Physiol.. 279. H2939-H2946 (2000)
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[Publications] Hirano, S., Imamura, T., Matsuo, T., Ishiyama, Y., Kato, J., Kitamura, K., Koiwaya, Y., and Eto, T.: "Differential responses of circulating and tissue adrenomedullin and gene expression to volume overload."J. Card. Fail.. 6. 120-129 (2000)
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