| Project/Area Number |
16590684
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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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 | Osaka University |
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Principal Investigator |
OHISHI Mitsuru Osaka University, Graduate School of Medicine, Assistant, 医学系研究科, 助手 (50335345)
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| Co-Investigator(Kenkyū-buntansha) |
OGIHARA Toshio Osaka University, Graduate School of Medicine, Professor, 医学系研究科, 教授 (60107042)
山本 浩一 大阪大学, 医学系研究科, 日本学術振興会特別研究員(DC)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2005: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2004: ¥3,000,000 (Direct Cost: ¥3,000,000)
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| Keywords | ACE2 / knockout mice / heart failure / survival ratio / AT1 receptor / MAP kinase / local RA system / heart failure death / TAC / 予後曲線 / ERK / JNK / AT1受容体拮抗薬 / 収縮障害 |
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| Research Abstract |
Angiotensin-converting enzyme 2 (ACE2) is a carboxypeptidase that cleaves angiotensin II to angiotensin 1-7. Recently, it was reported that mice lacking ACE2 (ACE2^<-/y> mice) exhibited reduced cardiac contractility. Because mechanical pressure overload activates the cardiac renin-angiotensin system, we used ACE2^<-/y> mice to analyze the role of ACE2 in the response to pressure overload. Twelve-week-old ACE2^<-/y> mice and wild-type (WT) mice received transverse aortic constriction (TAC) or sham operation. Sham-operated ACE2^<-/y> mice exhibited normal cardiac function and had morphologically normal hearts. In response to TAC, ACE2^<-/y>mice developed cardiac hypertrophy and dilatation. Furthermore, their hearts displayed decreased cardiac contractility and increased fetal cardiac gene induction, compared with WT mice. In response to chronic pressure overload, ACE2^<-/y> mice developed pulmonary congestion and increased incidence of cardiac death compared with WT mice. On a biochemical level, cardiac angiotensin II concentration and activity of mitogen-activated protein (MAP) kinases were markedly increased in ACE2^<-/y> mice in response to TAC. Administration of candesartan, an AT_1 subtype angiotensin receptor blocker, attenuated the hypertrophic response and suppressed the activation of MAP kinases in ACE2^<-/y> mice. Activation of MAP kinases in response to angiotensin II was greater in cardiomyocytes isolated from ACE2^<-/y> mice than in those isolated from WT mice. ACE2 plays an important role in dampening the hypertrophic response to pressure overload mediated by angiotensin II. Disruption of this regulatory function may accelerate cardiac hypertrophy and shorten the transition period from compensated hypertrophy to cardiac failure.
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