Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, PR China.
Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, PR China; Institute of Biomedical Sciences, Fudan University, Shanghai, PR China.
J Mol Cell Cardiol. 2018 Mar;116:125-134. doi: 10.1016/j.yjmcc.2018.01.018. Epub 2018 Feb 6.
Programmed cell death plays an essential role in myocardial homeostasis and pathology. Three distinct forms of programmed cell death have been identified, namely apoptosis, necrosis, and autophagic cell death. Necrosis, previously known as an unregulated form of cell death, has been recognized as a highly regulated process now and attracted great attention over the past decade. Programmed necrosis mainly refers to necroptosis, pyroptosis, ferroptosis, and mitochondrial permeability transition (MPT)-dependent necrosis. Among them, role of necroptosis and MPT-dependent necrosis in the pathogenesis of heart disease, mainly including myocardial infarction (MI), ischemia/reperfusion (I/R), and heart failure is well defined now. Necroptosis is orchestrated by a complex of proteins involving receptor-interacting protein kinase 1 (RIPK1), RIPK3 and mixed lineage kinase domain-like protein (MLKL). While MPT-dependent necrosis is another modality of necrosis characterized by MPT pore opening and cyclophilin-D (CypD)-dependent death signaling. Of note, the observed effects of necrostatin-1 (Nec-1, inhibitor of RIPK1) and cyclosporine A (CsA, inhibitor of CypD) on attenuating programmed necrosis and related cardiac injury further demonstrated the significant role of programmed necrosis in dictating cell demise and shed light on their further clinical application, along with other types of inhibitors targeting programmed necrosis. In this review, we summarized the recent progress on programmed necrosis in heart disease from molecular mechanisms to therapeutic strategies.
程序性细胞死亡在心肌稳态和病理中起着至关重要的作用。现已确定了三种不同形式的程序性细胞死亡，即细胞凋亡、坏死和自噬性细胞死亡。坏死，以前被认为是一种不受调节的细胞死亡形式，现在已被认为是一种高度受调节的过程，并在过去十年中引起了极大的关注。程序性坏死主要指坏死性凋亡、细胞焦亡、铁死亡和线粒体通透性转换（MPT）依赖性坏死。其中，坏死性凋亡和 MPT 依赖性坏死在心脏病发病机制中的作用，主要包括心肌梗死（MI）、缺血/再灌注（I/R）和心力衰竭，现在已经得到了很好的定义。坏死性凋亡是由涉及受体相互作用蛋白激酶 1（RIPK1）、RIPK3 和混合谱系激酶结构域样蛋白（MLKL）的蛋白质复合物所协调的。而 MPT 依赖性坏死是另一种以 MPT 孔开放和亲环素-D（CypD）依赖性死亡信号为特征的坏死方式。值得注意的是，使用坏死性凋亡抑制剂 1（Nec-1，RIPK1 的抑制剂）和环孢素 A（CsA，CypD 的抑制剂）观察到的对程序性坏死和相关心脏损伤的抑制作用进一步证明了程序性坏死在决定细胞死亡中的重要作用，并为其进一步的临床应用提供了启示，以及其他针对程序性坏死的抑制剂类型。在这篇综述中，我们总结了从分子机制到治疗策略的程序性坏死在心脏病中的最新进展。
