The role of ER stress and ubiquitin-proteasome system in the development of heart failrue
| Project/Area Number |
17590731
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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 |
MINAMINO Tetsuo Osaka University, Graduate School of Medicine, Assistant, 医学系研究科, 助手 (30379234)
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| Co-Investigator(Kenkyū-buntansha) |
TAKASHIMA Seiji Osaka University, Health care Center, Assistant, 保健センター, 助手 (90379272)
HORI Masatsugu Osaka University, Graduate School of Medicine, Professor, 医学系研究科, 教授 (20124779)
KITAKAZE Masafumi National Cardiovascular Center, Department of Cardiovascular Medicine, Director, 生理機能検査部, 部長(研究職) (20294069)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | ubiquitin / proteasome / heart failure / apoptosis / ER stress |
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| Research Abstract |
The endoplasmic reticulum (ER) is recognized as an organelle that participates in folding secretory and membrane proteins. The ER responds to stress by upregulating ER chaperones, but prolonged and/or excess ER stress leads to apoptosis. However, the potential role of ER stress in pathophysiological hearts remains unclear. Cardiac expression of ER chaperones was significantly increased 1 and 4 weeks after transverse aortic constriction (TAC), indicating that pressure overload by TAC induced prolonged ER stress. The CHOP-, but not JNK-or caspase-12-, dependent pathway was activated in failing hearts by TAC. Finally, mRNA levels of ER chaperones were markedly increased in failing hearts of patients. These findings suggest that pressure overload by TAC induces prolonged ER stress, which may contribute to cardiac myocyte apoptosis during progression from cardiac hypertrophy to failure. The ubiquitin-proteasome (U/P) system contributes to regulation of apoptosis degrading apoptosis-regulato
… More
ry proteins. Marked accumulation of ubiquitinated proteins in cardiomyocytes of human failing hearts suggested impaired U/P system in heart failure. Since cardiomyocyte apoptosis contributes to the progression of cardiac dysfunction in pressure-overloaded hearts, we investigated the role of U/P system in such conditions. Proteasome activities already depressed before the onset of cardiac dysfunction in pressure-overloaded hearts of mice. Cardiomyocyte apoptosis was observed along with depression of proteasome activities and elevation of proapoptotic/antiapoptotic protein ratio in failing hearts. In cultured cardiomyocytes, pharmacological inhibition of proteasome accumulated proapoptotic proteins such as p53 and Bax. Gene silencing of these proapoptotic proteins by RNA interference prevented the accumulation of respective proteins and attenuated cardiomyocyte apoptosis induced by proteasome inhibition. We conclude that depression of proteasome activities contributes to cardiac dysfunction resulting from cardiomyocyte apoptosis through accumulation of proapoptotic proteins by impaired degradation. We are now checking the interaction between ER stress and ubiquitin-proteasome system in failing hearts. Less
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Report
(3 results)
Research Products
(21 results)
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[Journal Article] S-nitrosylated and pegylated hemoglobin, a newly developed artificial oxygen carrier, exerts cardioprotection against ischemic hearts.2007
Author(s)
Asanuma H, Nakai K, Sanada S, Minamino T, Takashima S, Ogita H, Fujita M, Hirata A, Wakeno M, Takahama H, Kim J, Asakura M, Sakuma I, Kitabatake A, Hori M, Komamura K, Kitakaze M.
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Journal Title
J Mol Cell Cardiol. (In press)
Description
「研究成果報告書概要(欧文)」より
Related Report
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[Journal Article] Prolonged transient acidosis during early reperfusion contributes to the cardioprotective effects of postconditioning.2007
Author(s)
Fujita M, Asanuma H, Hirata A, Wakeno M, Takahama H, Sasaki H, Kim J, Takashima S, Tsukamoto O, Minamino T, Shinozaki Y, Tomoike H, Hori M, Kitakaze M.
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Journal Title
Am J Physiol Heart Circ Physiol. 292(4)
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Long-term stimulation of adenosine Alb receptors begun after myocardial infarction prevents cardiac remodeling in rats.2006
Author(s)
Wakeno M, Minamino T, Seguchi O, Okazaki H, Tsukamoto O, Okada K, Hirata A, Fujita M, Asanuma H, Kim J, Komamura K, Takashima S, Mochizuki N, Kitakaze M.
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Journal Title
Circulation. 114(18)
Pages: 1923-32
Description
「研究成果報告書概要(欧文)」より
Related Report
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[Journal Article] Erythropoietin enhances neovascularization of ischemic myocardium and improves left ventricular dysfunction after myocardial infarction in dogs.2006
Author(s)
Hirata A, Minamino T, Asanuma H, Fujita M, Wakeno M, Myoishi M, Tsukamoto O, Okada K, Koyama H, Komamura K, Takashima S, Shinozaki Y, Mori H, Shiraga M, Kitakaze M, Hori M.
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Journal Title
J Am Coll Cardiol. 48(1)
Pages: 176-84
Description
「研究成果報告書概要(欧文)」より
Related Report
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[Journal Article] Blockade of histamine H2 receptors protects the heart against ischemia and reperfusion injury in dogs.2006
Author(s)
Asanuma H, Minamino T, Ogai A, Kim J, Asakura M, Komamura K, Sanada S, Fujita M, Hirata A, Wakeno M, Tsukamoto O, Shinozaki Y, Myoishi M, Takashima S, Tomoike H, Kitakaze M.
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Journal Title
J Mol Cell Cardiol. 40(5)
Pages: 666-74
Description
「研究成果報告書概要(欧文)」より
Related Report
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