Departments of Medicine and Cell Biology, Wilf Family Cardiovascular Research Institute, Albert Einstein Cancer Center, and Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York; Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, New Jersey; Department of Internal Medicine 3, Division of Nephrology, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany; and Department of Physiology and Biophysics, University of Washington, Seattle, Washington.
Physiol Rev. 2019 Oct 1;99(4):1765-1817. doi: 10.1152/physrev.00022.2018.
Twelve regulated cell death programs have been described. We review in detail the basic biology of nine including death receptor-mediated apoptosis, death receptor-mediated necrosis (necroptosis), mitochondrial-mediated apoptosis, mitochondrial-mediated necrosis, autophagy-dependent cell death, ferroptosis, pyroptosis, parthanatos, and immunogenic cell death. This is followed by a dissection of the roles of these cell death programs in the major cardiac syndromes: myocardial infarction and heart failure. The most important conclusion relevant to heart disease is that regulated forms of cardiomyocyte death play important roles in both myocardial infarction with reperfusion (ischemia/reperfusion) and heart failure. While a role for apoptosis in ischemia/reperfusion cannot be excluded, regulated forms of necrosis, through both death receptor and mitochondrial pathways, are critical. Ferroptosis and parthanatos are also likely important in ischemia/reperfusion, although it is unclear if these entities are functioning as independent death programs or as amplification mechanisms for necrotic cell death. Pyroptosis may also contribute to ischemia/reperfusion injury, but potentially through effects in non-cardiomyocytes. Cardiomyocyte loss through apoptosis and necrosis is also an important component in the pathogenesis of heart failure and is mediated by both death receptor and mitochondrial signaling. Roles for immunogenic cell death in cardiac disease remain to be defined but merit study in this era of immune checkpoint cancer therapy. Biology-based approaches to inhibit cell death in the various cardiac syndromes are also discussed.
已经描述了十二种受调控的细胞死亡程序。我们详细回顾了其中九种的基本生物学特性，包括死亡受体介导的细胞凋亡、死亡受体介导的坏死（细胞坏死）、线粒体介导的细胞凋亡、线粒体介导的坏死、自噬依赖性细胞死亡、铁死亡、细胞焦亡、Parthanatos 和免疫原性细胞死亡。接下来，我们剖析了这些细胞死亡程序在主要心脏综合征（心肌梗死和心力衰竭）中的作用。与心脏病最相关的重要结论是，受调控的心肌细胞死亡形式在再灌注（缺血/再灌注）心肌梗死和心力衰竭中都发挥着重要作用。虽然凋亡在缺血/再灌注中可能发挥作用，但通过死亡受体和线粒体途径的受调控的坏死形式是至关重要的。铁死亡和 Parthanatos 在缺血/再灌注中也可能很重要，尽管尚不清楚这些实体是作为独立的死亡程序还是作为坏死细胞死亡的放大机制发挥作用。细胞焦亡也可能导致缺血/再灌注损伤，但可能是通过对非心肌细胞的影响。通过凋亡和坏死导致的心肌细胞丢失也是心力衰竭发病机制的一个重要组成部分，并且通过死亡受体和线粒体信号传导介导。免疫原性细胞死亡在心脏疾病中的作用仍有待确定，但在免疫检查点癌症治疗的时代，值得在这方面进行研究。我们还讨论了基于生物学的方法来抑制各种心脏综合征中的细胞死亡。
