2002 Fiscal Year Final Research Report Summary
Pathophysiological Role of Adrenomedullin in Cardiovascular Disease and Therapeutic Application of Adrenomedullin
| Project/Area Number |
10218208
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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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) |
KATO Johji Miyazaki Medical College, 1st Dept Intern Med, Research Associate, 医学部, 助手 (20274780)
IMAMURA Takuroh Miyazaki Medical College, 1st Dept Intern Med, Lecturer, 医学部, 講師 (60203329)
KANNAN Hiroshi Miyazaki Medical College, 1st Dept Physiol, Professor, 医学部, 教授 (00049058)
KURIHARA Hiroki Kumamoto University, Dept. Embryogenesis, Professor, 発生医学研究センター, 教授 (20221947)
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| Project Period (FY) |
1998 – 2002
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| Keywords | adrenomedullin / locally-acting hormone / central action / gene manipulation / intermediate form / CRLR / RAMP / therapeutic application |
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| Research Abstract |
Aim of this study : This research project was planned to clarify the pathophysiological role of adrenomedullin (AM) in cardiovascular diseases and to test the possibility of this peptide being used for these diseases. Results : (1) The in vitro and in vivo studies showed that AM acts as an autocrine or paracrine factor inhibiting hypertrophy of cardiomyocytes and proliferation of cardiac fibroblasts and that AM production in cardiac ventricle is increased by angiotensin II and by mechanical load to the heart. (2) Cerebroventricular infusion of AM increased blood pressure and heart rate in conscious rats, suggesting a central role of AM in the cardiovascular regulation. (3) The findings from AM gene transgenic and knockout mice showed that AM is essential in embryonic development of the vascular system and that endogenous AM functions to protect the cardiovascular system in hypertension, septic shock and progression of atherosclerosis. (4) Extracellular domains of RAMPs essential for receptor binding were identified, and the mutant RAMPs without these portions were found to act as dominant negative RAMPs. (5) The major molecular form of AM in human plasma was found to be AM-Gly, an intermediate form. The ex vivo experiments showed that the intermediate form AM-Gly dilates rat aorta following conversion to mature AM in aortic tissue. (6) Both the mature and intermediate form of AM was found to increase in plasma of patients with hypertension and heart failure. (7) Chronic infusion of recombinant AM inhibited left ventricular remodeling, improving cardiac function in rats with myocardial infarction. Conclusion : The present findings suggest that AM function as a locally-acting or circulating hormone counteracting progression of cardiovascular diseases, suggesting a possibility of therapeutic application of this peptide.
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[Publications] Cao, Y., Kitamura, K., Ito, K., Kato, J., Hashida, S., Morishita, K., and Eto, 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 RAMP 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] Imai, Y., Shindo, T., Sata, M., Memura, K., Saito, Y., Akishita, M., Osuga, J., Ishibashi, S., Tobe, K., Maekawa, H., Oh-hashi, Y., Morita, H., Kurihara, Y., Yazaki, Y.,Nagai, R., Kurihara, H.: "Resistance to neointimal hyperplasia and fatty streak formation in adrenomedullin overexpression mice"Arterioscler. Thromb. Vasc. Biol.. 22. 1310-1315 (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] Shindo, T., Kurihara, Y., Nishimatsu, H., Moriyama, N., Kakoki, M., Wang, Y., Imai, Y., Ebihara, A., Kuwaki, T., Ju, K-H., Minamino, N., Kangawa, K., Ishikawa, T., Fukuda, M., Akimoto, Y., Kawakami, H., Imai, T., Morita, H., Yazaki, Y, Nagai, R., Hirata, Y., and Kurihara, H.: "Vascular abnormalities and elevated blood pressure in mice lacking adrenomedullin gene"Circulation. 104. 1964-1971 (2001)
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[Publications] Kitamura, K., Matsui, E., Kato, J., Kato, F., Kite, 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 amino 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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