| Project/Area Number | 09670748 |
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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 | Keio University |
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Principal Investigator |
YOSHIKAWA Tsutomu Keio University Dept of Med Assistant Professor, 医学部, 講師 (20174906)
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| Co-Investigator(Kenkyū-buntansha) |
TAKAHASHI Toshiyuki Keio University Dept of Med, 医学部, 助手 (20286470)
IWATA Michikado Keio University Dept of Med, 医学部, 助手 (30276224)
ANZAI Toshihisa Keio University Dept of Med, 医学部, 助手 (60232089)
MAEKAWA Yuichiro Keio University Dept of Med, 医学部, 助手 (90296575)
中村 岩男 慶應義塾大学, 医学部, 助手 (60265808)
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| Project Period (FY) |
1997 – 2000
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| Project Status |
Completed(Fiscal Year 2000)
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| Budget Amount *help |
¥3,100,000 (Direct Cost : ¥3,100,000)
Fiscal Year 2000 : ¥700,000 (Direct Cost : ¥700,000)
Fiscal Year 1999 : ¥500,000 (Direct Cost : ¥500,000)
Fiscal Year 1998 : ¥500,000 (Direct Cost : ¥500,000)
Fiscal Year 1997 : ¥1,400,000 (Direct Cost : ¥1,400,000)
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| Keywords | β-adrenergic receptor / cardiomyopathy / myocardial infarction / remodeling / guanine nucleotide binding protein / cardiac hypertrophy / G-protein-coupled receptor kinase / uncoupling / 心不全 / β受容体 |
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| Research Abstract |
We produced two animal models for heart failure including autoimmune-mediated cardiomyopathy induced by β1-adrenergic receptors as a nonischemic cardiomyopathy in rabbits and myocardial infarction as an ischemic cardiomyopathy in rats. In autoimmune-mediated cardiomyopathy, left ventricle exhibited concentric hypertrophy with myocyte hypertrophy, myofiber disorganization, and interstitial fibrosis. Uncoupling of β-adrenergic receptors was based on increases in inhibitory G-protein and type 5 G-protein-coupled receptor kinase (GRK). These phenomena were prevented by bisoprolol treatment. Immunoglobulin G fraction isolated from this rabbits has an intrinsic agonisitic effect, which was inhibited by inverse agonist, bisoprolol in a dosedependent manner. Thus, in this model, autoantibody produced by autoimmunity appears to produced cardiac hypertrophy and signaling abnormalities through acting as an agonist.
We noted that heart failure was induced through remodeling by 6 weeks after coronary artery occlusion of left anterior descending artery in rats. GRK type 2 and protein kinase C ipsilon (PKCε) isoform were both increased as well as uncoupling of β-adrenergic receptors. Short-tem use of angiotensin II type 1 receptor antagonist inhibited the increases in GRK type 2 and PKCε resulting in a reversal of adrenergic receptor uncoupling. These data suggested that activation in renin-angiotensin system induced uncoupling of β1-adrenergic receptor through intracellular crosstalk, contributing over heart failure in the model.
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