| Project/Area Number |
11557047
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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 | 展開研究 |
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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, Institute of Clinical Mediated, Assistant Professor, 臨床医学系, 講師 (60222329)
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| Co-Investigator(Kenkyū-buntansha) |
SAKURAI Takeshi University of Tsukuba, Institute of Basic Medical Sciences, Associate Professor, 基礎医学系, 助教授 (60251055)
GOTO Katsutoshi University of Tsukuba, Institute of Basic Medical Sciences, Professor, 基礎医学系, 教授 (30012660)
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| Project Period (FY) |
1999 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥13,500,000 (Direct Cost: ¥13,500,000)
Fiscal Year 2001: ¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2000: ¥5,000,000 (Direct Cost: ¥5,000,000)
Fiscal Year 1999: ¥5,100,000 (Direct Cost: ¥5,100,000)
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| Keywords | endothelin / heart failure / molecular pharmacology / molecular biology / energy metabolism disturbance / cardioprotection / cardrovascular substances / failing heart / 心臓血管作動性物質 / 分子循環器病学 / 心筋細胞 / 薬理学 / 心肥大 |
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| Research Abstract |
Endothelin (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 β -myosin heavy chain) and of functional molecular markers (eg, mRNA levels of ryanodine receptor, sarcoplasmic reticulum Ca^<2+>-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 phorbokester-sensitive c-fos and c-jun complexes, binding sites for nuclear factor-i, AP-1, and GATA proteins. The following mechanism is also suggested to be involved. In the failing heart, principal ATP generation by mitochondrial β-oxidation is impaired and adaptively switched to glycolysis. Hypoxialnducible factor (HIF)-1 α is an important transcriptional factor which activates gene expression of glycolytic enzymes. We find a H IF-i a 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-I expression through a transcriptional activation by ET-1 α, which leads to aggravation of heart failure.
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