Death Receptor Signaling in the Heart
Authors: Dulguun Amgalan, Yun Chen, Richard N. Kitsis
Journal: Circulation (2017)

esearch over the past 3 decades has established that loss of cardiomyocytes through regulated cell suicide mechanisms contributes critically to the pathogenesis of myocardial infarction, heart failure, and other cardiac syndromes. 1wo of the most important cell death programs in the context of heart disease are apoptosis and necrosis.These forms of cell death differ primarily with respect to the magnitude of collateral damage inflicted on surrounding tissue.In apoptosis, the plasma membrane remains intact until the dying cell undergoes phagocytosis, whereas in necrosis not only does the membrane become leaky, but the cell actively secretes proinflammatory molecules.Apoptosis has always been recognized as a gene-directed and regulated process.In contrast, necrosis was thought to be an uncontrolled form of cell death resulting from overwhelming physical and chemical trauma to a cell.A big surprise over the past 15 years, however, has been the realization that a significant proportion of necrotic cell deaths occurs through highly regulated mechanisms.Both apoptosis and necrosis can be initiated through 2 major pathways: 1 involving mitochondria and the other cell surface death receptors (Figure ,A).In this issue of Circulation, Guo et al 2 utilize multiple mouse genetic models to dissect the death receptor pathway in the heart.The most important finding in this study is that knockout of the gene encoding tumor necrosis factor receptor-associated factor 2 (TRAF2), a protein in this pathway, results in dilated cardiomyopathy through unleashing apoptotic and necrotic cardiomyocyte death.The death receptor pathway is initiated by various ligands of the tumor necrosis factor (TNF) family. 3The present study focuses on binding of TNF-α to TNF receptor 1. Depending on other signals and conditions in the cell, this may promote cell survival, apoptosis, or a regulated form of necrosis, which in this pathway is referred to as necroptosis (Figure ,B).Cell survival is stimulated by TNF-α-induced recruitment of proteins into complex I at the plasma membrane.Complex I, however, can morph into several cytoplasmic protein complexes, including complexes IIa and IIb, which induce apoptosis, and complex IIc, which signals necroptosis.The molecular regulation of these transitions is incompletely understood, but deubiquitylation plays an important role in the disassembly of complex I and loss of cell survival signals.A major factor in the choice of necroptotic over apoptotic cell death is the inhibition of caspases, which are proteases required for apoptosis.Molecular details regarding the death receptor pathway are provided in the figure legend.Guo et al 2 used multiple genetic mouse models, cultured mouse embryonic fibroblasts, and primary cardiomyocytes to define the role of TRAF2, an E3-ubiquitin ligase, in the heart.The data show that myocardial TRAF2 levels increase significantly in response to various cardiac stresses (eg, pressure overload and myocardial infarction).Moreover, cardiomyocyte-specific deletion of TRAF2 elicits a severe dilated cardiomyopathy even in the absence of superimposed cardiac stress.This is Death Receptor Signaling in the Heart Cell Survival, Apoptosis, and Necroptosis