Depression of proteasome activities during the progression of cardiac dysfunction in pressure-overloaded heart of mice

被引:124
作者
Tsukamoto, O
Minamino, T
Okada, K
Shintani, Y
Takashima, S
Kato, H
Liao, YL
Okazaki, H
Asai, M
Hirata, A
Fujita, M
Asano, Y
Yamazaki, S
Asanuma, H
Hori, M
Kitakaze, M [1 ]
机构
[1] Natl Cardiovasc Ctr, Dept Cardiovasc Med, Suita, Osaka 5658565, Japan
[2] Osaka Univ, Grad Sch Med, Dept Cardiovasc Med, Suita, Osaka 5650871, Japan
基金
日本学术振兴会;
关键词
ubiquitin-proteasome; apoptosis heart failure; protein degradation;
D O I
10.1016/j.bbrc.2005.12.120
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The ubiquitin-proteasome system contributes to regulation of apoptosis degrading apoptosis-regulatory proteins. Marked accumulation of ubiquitinated proteins in cardiomyocytes of human failing hearts suggested impaired Ubiquitin-proteasome system in heart failure. Since cardiomyocyte apoptosis contributes to the progression of cardiac dysfunction in pressure-overloaded hearts, we investigated the role of ubiquitin-proteasome system in such conditions. We found that 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. (c) 2005 Elsevier Inc. All rights reserved.
引用
收藏
页码:1125 / 1133
页数:9
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