Proteasome inhibition attenuates heart failure during the late stages of pressure overload through alterations in collagen expression
Proteasome inhibition attenuates heart failure during the late stages of pressure overload through alterations in collagen expression
复制标题
蛋白酶体抑制通过改变胶原表达来减轻压力超负荷晚期的心力衰竭
DOI：
10.1016/j.bcp.2012.10.025
复制
发表时间：
2013-01-15
影响因子：
5.8
通讯作者：
Dong, Yugang
中科院分区：
文献类型：
--
作者：
Ma, Yuedong;Chen, Yili;Dong, Yugang
尽管泛素-蛋白酶体系统(UPS)在压力超负荷所致心肌肥厚中的作用一直被研究，但UPS在心肌纤维化中的基础作用却鲜有人关注。我们先前的研究发现，在压力超负荷的早期和中期，蛋白酶体抑制剂(MG132)治疗可以减轻心脏纤维化和心力衰竭。然而，这种抑制剂对晚期压力超负荷心脏的影响仍不清楚，也存在争议。本研究旨在探讨MG132在压力超负荷晚期对心脏纤维化和功能障碍的影响及其可能机制。采用腹主动脉缩窄(AAC)或假手术的雄性SD大鼠，给予MG132(0.1 mg kg(-1)天(-1))或赋形剂，连续16周。在研究结束时评价左心功能、胶原沉积和Ang II水平。采用血管紧张素Ⅱ刺激的成年大鼠心脏成纤维细胞，观察MG132对胶原合成的影响及肾素-血管紧张素-醛固酮系统(RAAS)与UPS的关系。在压力超负荷的晚期，MG132治疗通过抑制心肌纤维化而不是抑制心肌肥厚来减轻心功能不全。我们还发现，Ang II激活心脏中的UPS，MG132通过抑制核因子-kappa B/转化生长因子-β/Smad2信号通路来抑制Ang II诱导的胶原合成。因此，抑制蛋白酶体可以提供一种新的有希望的治疗策略，以防止心脏纤维化和心力衰竭的进展，即使在压力超负荷的晚期也是如此。(C)2012 Elsevier Inc.保留所有权利。
Although the role of the ubiquitin-proteasome system (UPS) in cardiac hypertrophy induced by pressure overload has been consistently studied, the fundamental importance of the UPS in cardiac fibrosis has received much less attention. Our previous study found that proteasome inhibitor (MG132) treatment attenuated cardiac fibrosis and heart failure during the early and middle stages of pressure overload. However, the effects of this inhibitor on late-stage pressure overload hearts remain unclear and controversial. The present study was designed to investigate the effects and possible mechanisms of MG132 on cardiac fibrosis and dysfunction during the late stages of pressure overload. Male Sprague Dawley rats with abdominal aortic constriction (AAC) or a sham operation received an intraperitoneal injection of MG132 (0.1 mg kg(-1) day(-1)) or vehicle for 16 weeks. Left ventricular (LV) function, collagen deposition and Ang II levels were evaluated at study termination. Ang II-stimulated adult rat cardiac fibroblasts were utilized to examine the effects of MG132 on collagen synthesis and the relationship between the renin-angiotensin-aldosterone system (RAAS) and the UPS. MG132 treatment attenuated ventricular dysfunction by suppressing cardiac fibrosis rather than inhibiting cardiac hypertrophy during the late-stages of pressure overload. We also found that Ang II activates UPS in the heart and MG132 attenuates Ang II-induced collagen synthesis via suppression of the NF-kappa B/TGF-beta/Smad2 signaling pathways. Proteasome inhibition therefore could provide a new promising therapeutic strategy to prevent cardiac fibrosis and progression of heart failure even during the late-stages of pressure overload. (C) 2012 Elsevier Inc. All rights reserved.