| 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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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥135,900,000 (Direct Cost: ¥135,900,000)
Fiscal Year 2002: ¥29,700,000 (Direct Cost: ¥29,700,000)
Fiscal Year 2001: ¥29,700,000 (Direct Cost: ¥29,700,000)
Fiscal Year 2000: ¥22,500,000 (Direct Cost: ¥22,500,000)
Fiscal Year 1999: ¥27,000,000 (Direct Cost: ¥27,000,000)
Fiscal Year 1998: ¥27,000,000 (Direct Cost: ¥27,000,000)
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| Keywords | adrenomedullin / locally-acting hormone / central action / gene manipulation / intermediate form / CRLR / RAMP / therapeutic application / アミド化酵素 / 局所調節因子 / AM遺伝子過剰発現マウス / 心筋細胞 / 心線維芽細胞 / AM遺伝子欠損マウス / コンビナントAM / IRMA / PAMP / 生理活性ペプチド / 新規生理活性ペプチド / アンジオテンシンII / C-キナーゼ / AM-Gly(iAM) / 心筋の蛋白合成 / 受容体 / ラジオイムノアッセイ / 循環調節因子 / 血管作動性ペプチド / C末端アミド化 |
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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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