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The role of ER stress and ubiquitin-proteasome system in the development of heart failrue

内质网应激和泛素蛋白酶体系统在心力衰竭发生中的作用

基本信息

批准号：
17590731
负责人：
MINAMINO Tetsuo
金额：
$ 2.24万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590731/
关键词：
ubiquitin proteasome heart failure apoptosis ER stress

项目摘要

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

内质网（ER）被认为是参与折叠分泌蛋白和膜蛋白的细胞器。内质网通过上调内质网伴侣来应对应激，但长期和/或过度的内质网应激会导致细胞凋亡。然而，内质网应激在病理生理心脏中的潜在作用仍不清楚。横主动脉缩窄 (TAC) 后 1 周和 4 周，心脏中 ER 伴侣的表达显着增加，表明 TAC 造成的压力超负荷导致了长时间的 ER 应激。 TAC 在衰竭的心脏中激活了 CHOP- 依赖性途径，但 JNK- 或 caspase-12- 依赖性途径不被激活。最后，心脏衰竭患者中 ER 伴侣的 mRNA 水平显着增加。这些发现表明，TAC 造成的压力超负荷会导致内质网应激延长，这可能会导致心肌肥大到衰竭过程中心肌细胞凋亡。泛素蛋白酶体 (U/P) 系统有助于细胞凋亡的调节，降解细胞凋亡调节蛋白。人类衰竭心脏的心肌细胞中泛素化蛋白的显着积累表明心力衰竭中 U/P 系统受损。由于心肌细胞凋亡会导致压力超负荷心脏中心功能障碍的进展，因此我们研究了 U/P 系统在这种情况下的作用。在压力超负荷的小鼠心脏出现心功能障碍之前，蛋白酶体活性就已经减弱。在衰竭的心脏中观察到心肌细胞凋亡以及蛋白酶体活性的抑制和促凋亡/抗凋亡蛋白比率的升高。在培养的心肌细胞中，蛋白酶体的药理抑制会积累促凋亡蛋白，例如 p53 和 Bax。通过 RNA 干扰对这些促凋亡蛋白进行基因沉默，可防止相应蛋白的积累，并减弱蛋白酶体抑制诱导的心肌细胞凋亡。我们得出的结论是，蛋白酶体活性的抑制会导致心肌细胞凋亡，通过受损的降解导致促凋亡蛋白的积累，从而导致心脏功能障碍。我们现在正在检查衰竭心脏中内质网应激和泛素蛋白酶体系统之间的相互作用。较少的

项目成果

期刊论文数量（21）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Annual Review　循環器

年度回顾：循环系统

DOI：
发表时间：
2014
期刊：
影响因子：
0
作者：
Takenouchi T;Nabetani M;Iwata O;Tamura M;野々木宏・田原良雄・武田聡・黒田泰弘・笠岡俊志・有元秀樹ほか;永山正雄;永山正雄;梁成勲・永山正雄;永山正雄;坂田隆道・小室一成・佐地勉・野々木宏ほか
通讯作者：
坂田隆道・小室一成・佐地勉・野々木宏ほか

Erythropoietin enhances neovascularization of ischemic myocardium and improves left ventricular dysfunction after myocardial infarction in dogs