| Project/Area Number |
12470147
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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 | University of Tsukuba |
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Principal Investigator |
MIYAUCHI Takashi University of Tsukuba, Professon of Institute of Clinical Medicine, 教授 (60222329)
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| Co-Investigator(Kenkyū-buntansha) |
GOTO Katsutoshi University of Tsukuba, Professon of Institute of Basic Medical Sciences, 教授 (30012660)
SAKURAI Takeshi University of Tsukuba, Associate Professon of Institute of Basic Medical Sciences, 助教授 (60251055)
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| Project Period (FY) |
2000 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥14,100,000 (Direct Cost: ¥14,100,000)
Fiscal Year 2002: ¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2001: ¥5,000,000 (Direct Cost: ¥5,000,000)
Fiscal Year 2000: ¥5,700,000 (Direct Cost: ¥5,700,000)
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| Keywords | heart failare / endothelin / antagonist / pharmacology / phtsiology / mclesular biology / gene expression / cardiac hypeitrsphy / 分子循環器学 / 薬理学 / 病態生理学 / エネルギー代謝 / 循環薬理学 / 病状悪化 |
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| Research Abstract |
In the present study, we studied the pathophysiological roles of endothelin-1 (ET-1) in heart failure by molecular biological and pharmaco-physiological approach. ET-1 induces myocardial hypertrophy and causes cellular injury in cardiac myocytes. The production of ET-1 is markedly increased in the failing heart and chronic treatment with an ET receptor antagonist greatly improves the survival rate of animals with CHF. An ET antagonist improves the alteration in the expression of various cardiac genes of classic molecular markers (eg, mRNA in ANP and 13 -myosin heavy chain) and of functional molecular markers (eg, mRNA levels of ryanodine receptor, sarcoplasmic reticulum calcium-ATPase) in the failing heart, suggesting that the great improvement of survival in CHF animals by an ET antagonist is partly attributed to the prevention of molecular changes in the failing heart. Several molecular mechanisms are considered to be involved in the marked increase in ET-1 expression in the failing heart. The transcription of the ET-1 gene is regulated through the phorbol-ester-sensitive c-fos and c-jun complexes, binding sites for nuclear factor-1, AP-1, and GATA proteins. In the failing heart, principal ATP generation by mitochondrial β-oxidation is impaired and adaptively switched to glycolysis. Hypoxia-inducible factor (HIF)-1α is an important transcriptional factor which activates gene expression of glycolytic enzymes. We find a HIF-1α binding site in 5'-regulatory region of ET-1 gene. Our data revealed a novel molecular mechanism of up-regulation of cardiac ET-1 in heart failure that the impairment of cardiac energy metabolism is involved in a marked increase in ET-1 expression through a transcriptional activation by HIF-1α. We also revealed that ET-1 induced cardiac hypertrophy is inhibited by activation of PPAR a partly via c-Jun NH2-terminal-kinase pathway. The present study showed that ET-1 plays important roles in worsening heart failure.
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