| Project/Area Number |
17590719
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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 | Nagoya University |
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Principal Investigator |
CHENG Xianwu Nagoya University, School of Medicine, Research Associate, 医学部, 助手 (30378228)
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| Co-Investigator(Kenkyū-buntansha) |
KAZUYA Masafumi Nagoya University, Graduate School of Medicine, Associate Professor, 大学院医学系研究科, 助教授 (10283441)
NAGATA Kouzou Nagoya University, School of Medicine, Associate Professor, 医学部, 助教授 (20378227)
KONDO Takahisa University Hospital, Assistant Professor, 医学部附属病院, 講師 (00303644)
IGUCHI Aakihisa Nagoya University, Graduate School of Medicine, Professor, 大学院医学系研究科, 教授 (20109763)
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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 |
¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 2006: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | Ventricular Remodeling / Protease-Cathepsin S / Hypertension / Heart Failure / Cardiomyocyte / Olmesartan / 蛋白質分解酵素-カテプシンS |
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| Research Abstract |
Background : Cathepsin activation contributes to tissue remodeling in several disease states. The present study tested the hypothesis that cathepsin inhibition prevents LV remodeling and dysfunction in the development of CHF associated with hypertension.
Methods and Results : Dahl salt-sensitive rats fed an 8% NaCl diet from age 7 weeks served as a CHF model arbitrarily assigned to three treatment groups at age 12 weeks. The abundance of cathepsin mRNAs and proteins localized in cardiac myocytes (CMCs) and cathepsin-dependent activities were increased in the left ventricle of CHF rats, and were reduced by olmesartan treatment. Olmesartan suppressed the elastic lamina degradation concomitant with decreased local cathepsin S expression in intracoronary smooth muscle cells (SMCs) and restored the ratio of elastin to collagen in CHF rats. Furthermore, olmesartan suppressed not only interleukin-1β expression and macrophage infiltration but also levels of NADPH oxidase components (p22^<phox>, gp91^<phox>, and p47^<phox>) concomitant with decreased NADPH activity and O_2^- production in CHF rats. These were accompanied by improved cardiac fibrosis, stiffness, and dysfunction. Interestingly, all of these improvements were observed by E64d. The antioxidants MnTmPyp and N-acetylcysteine inhibited the H2O2-induced increase in cathepsin expression and elastolytic activity in culture CMCs and SMC.
Conclusions : These results suggest that cathepsins are likely to trigger and promote LV remodeling, and that olmesartan-mediated inhibition of angiotensin type1 receptor inhibits cathepsins by suppressing inflammation and oxidative stress, leading to the prevention of cardiac remodeling and dysfunction.
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