Necroptotic cell death in failing heart: relevance and proposed mechanisms
Necroptotic cell death in failing heart: relevance and proposed mechanisms
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心力衰竭中坏死性细胞死亡的相关性及机制探讨
DOI：
10.1007/s10741-016-9537-8
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发表时间：
2016-03-01
影响因子：
4.6
通讯作者：
Dhalla, Naranjan S.
中科院分区：
文献类型：
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作者：
Adameova, Adriana;Goncalvesova, Eva;Dhalla, Naranjan S.
由于心肌细胞的增殖、更新和修复能力有限，心脏细胞的损失随后被纤维组织替代被认为会导致心室功能障碍并进展为心力衰竭（HF）。传统上认为心力衰竭中心肌细胞的损失主要是由于程序性细胞凋亡或不受调节的坏死所致。虽然正在进行广泛的研究工作来确定这两种细胞死亡方式在心力衰竭发展中的确切意义和贡献，但最近的知识表明，在衰竭的心脏中存在一种不同形式的细胞死亡，称为坏死性凋亡，并且具有重要性。这种新的细胞损伤过程类似于被动坏死和适应不良自噬的一些形态特征，是一个程序化过程，由一组复杂的蛋白质精心策划，包括受体相互作用蛋白激酶 1 和 3 (RIP1、RIP3) 以及混合谱系激酶结构域样蛋白 (MLKL)。 RIP1-RIP3-MLKL 信号通路的激活会导致阳离子稳态破坏、质膜破裂，最终导致细胞死亡。抑制该途径中的任何位点似乎可能被证明是预防衰竭心脏中坏死性细胞死亡的有效药理学干预措施。本综述旨在描述与坏死性凋亡相关的信号通路的一般方面，描述其与某些心脏损伤模型中心脏功能障碍的关系，并讨论其在各种类型心力衰竭中潜在病理机制的潜在相关性。
As cardiomyocytes have a limited capability for proliferation, renewal, and repair, the loss of heart cells followed by replacement with fibrous tissue is considered to result in the development of ventricular dysfunction and progression to heart failure (HF). The loss of cardiac myocytes in HF has been traditionally believed to occur mainly due to programmed apoptosis or unregulated necrosis. While extensive research work is being carried out to define the exact significance and contribution of both these cell death modalities in the development of HF, recent knowledge has indicated the existence and importance of a different form of cell death called necroptosis in the failing heart. This new cell damaging process, resembling some of the morphological features of passive necrosis as well as maladaptive autophagy, is a programmed process and is orchestrated by a complex set of proteins involving receptor-interacting protein kinase 1 and 3 (RIP1, RIP3) and mixed lineage kinase domain-like protein (MLKL). Activation of the RIP1-RIP3-MLKL signaling pathway leads to disruption of cation homeostasis, plasma membrane rupture, and finally cell death. It seems likely that inhibition of any site in this pathway may prove as an effective pharmacological intervention for preventing the necroptotic cell death in the failing heart. This review is intended to describe general aspects of the signaling pathway associated with necroptosis, to describe its relationship with cardiac dysfunction in some models of cardiac injury and discuss its potential relevance in various types of HF with respect to the underlying pathologic mechanisms.