Programmed necrosis in cardiomyocytes: mitochondria, death receptors and beyond

Abstract

Excessive death of cardiac myocytes leads to many cardiac diseases, including myocardial infarction, arrhythmia, heart failure and sudden cardiac death. For the last several decades, most work on cell death has focused on apoptosis, which is generally considered as the only form of regulated cell death, whereas necrosis has been regarded to be an unregulated process. Recent findings reveal that necrosis also occurs in a regulated manner and that it is closely related to the physiology and pathophysiology of many organs, including the heart. The recognition of necrosis as a regulated process mandates a re‐examination of cell death in the heart together with the mechanisms and therapy of cardiac diseases. In this study, we summarize the regulatory mechanisms of the programmed necrosis of cardiomyocytes, that is, the intrinsic (mitochondrial) and extrinsic (death receptor) pathways. Furthermore, the role of this programmed necrosis in various heart diseases is also delineated. Finally, we describe the currently known pharmacological inhibitors of several of the key regulatory molecules of regulated cell necrosis and the opportunities for their therapeutic use in cardiac disease. We intend to systemically summarize the recent progresses in the regulation and pathological significance of programmed cardiomyocyte necrosis along with its potential therapeutic applications to cardiac diseases. Linked Articles This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc

Salvianolic Acid B Promotes the Survival of Random-Pattern Skin Flaps in Rats by Inducing Autophagy

“…Thus, we analyzed apoptosis in areas of ischemia in the skin flaps. Mitochondria are centrally located during apoptosis ( Zhang et al, 2018 ). Bax induces permeabilization of the mitochondrial outer membrane, leading to swelling ( Wei et al, 2018 ).…”

ADP-ribosylation: from molecular mechanisms to human disease

“…PARP1-dependent cell death via parthanatos has been implicated in several critical pathological processes, such as ischemia-reperfusion injury in myocardial infarction and stroke, septic shock, brain trauma and neurodegenerative diseases such as Parkinsons disease and Alzheimers disease (Pacher and Szabo, 2007;Moroni, 2008;Lee et al, 2013;Dawson and Dawson, 2017;Berger et al, 2018;Henning et al, 2018;Kam et al, 2018;Zhang, J. et al, 2018). A common theme among these disorders seems to be PARP1 hyperactivation in response to oxidative DNA damage, either as part of the reperfusion of oxygen-deprived tissues or caused by pathophysiological changes that induce the production of reactive oxygen species or nitric oxide.…”

Astaxanthin Protects Ochratoxin A-Induced Oxidative Stress and Apoptosis in the Heart via the Nrf2 Pathway

“…Oxidative stress has been shown to cause apoptosis [35,36], and it is well-known that apoptosis is a process of selective cell death [37,38]. A number of mycotoxins and heavy metals can cause extensive cardiomyocyte apoptosis [31,39,40].…”

“…According to previous studies, apoptosis in the myocardium is mainly mitochondrial apoptosis. Bax and Bcl-2 are two important proteins that respond to mitochondrial apoptosis; Bax is a proapoptotic protein, and Bcl-2 is an antiapoptotic protein [38,43]. In addition, myocardial injury in rats causes apoptosis by activating the caspase family [44][45][46].…”