The bitter end - The ubiquitin-proteasome system and cardiac dysfunction
The bitter end - The ubiquitin-proteasome system and cardiac dysfunction
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DOI：
10.1161/circulationaha.106.649863
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发表时间：
2007-03-20
期刊：
影响因子：
37.8
通讯作者：
Willis, Monte S.
中科院分区：
文献类型：
--
作者：
Patterson, Cam;Ike, Christopher;Willis, Monte S.
许多因素导致充血性心力衰竭：灌注变化、血流动力学应激、钙代谢改变和细胞信号传导途径失调。对这些过程的干预构成了当前心力衰竭治疗的基础。尽管如此，心力衰竭主要是一种磨损性疾病;尽管我们对心脏生理学和心力衰竭的临床表现有所了解，但只有在极少数情况下，心力衰竭的治疗才能使心脏功能正常化。蛋白质特别容易受到心脏磨损的影响，因为它们是压力感知和力量产生的主要机制。最近的证据支持蛋白质损伤和受损蛋白质清除受损在人类心力衰竭综合征的病理生理学中的作用。监测和保护心肌细胞免受受损蛋白积累的过程被称为蛋白质质量控制，分子伴侣和泛素-蛋白酶体系统是该过程的主要效应子。蛋白质质量控制策略的见解可能会导致关于预防和治疗人类心力衰竭的新概念。本文综述了这些途径及其在人类心力衰竭综合征中的已知和假定作用，重点是提供对这些基本机制的临床导向理解。
Many elements contribute to congestive heart failure: changes in perfusion, hemodynamic stresses, alterations in calcium metabolism, and dysregulation of cell signaling pathways. Intervention in these processes forms the basis for current heart failure therapies. Nevertheless, heart failure is primarily a disease of wear and tear; despite everything we know about cardiac physiology and the clinical manifestations of heart failure, only in rare instances does therapy for heart failure normalize cardiac function. Proteins are especially prone to the forces of wear and tear in the heart because they are the primary mechanisms for stress sensing and force generation. Recent evidence supports a role for protein damage and impaired clearance of damaged proteins in the pathophysiology of human heart failure syndromes. The process of monitoring and protecting cardiac cells from accumulation of damaged proteins is known as protein quality control, and the molecular chaperone and ubiquitin-proteasome systems are the primary effectors of this process. Insights from protein quality-control strategies may lead to new concepts about prevention and treatment of human heart failure. This review provides a general overview of these pathways and their known and postulated roles in human heart failure syndromes, with a focus on providing a clinically oriented understanding of these fundamental mechanisms.