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Circulation. 2017;136:743746. DOI: 10.1161/CIRCULATIONAHA.117.029566 August 22, 2017743 EDITORIAL Dulguun Amgalan, MS Yun Chen, PhD Richard N. Kitsis, MD EDITORIAL Article, see p 729 R esearch over the past 3 decades has established that loss of cardiomyocytes through regulated cell suicide mechanisms contributes critically to the patho- genesis of myocardial infarction, heart failure, and other cardiac syndromes.1 Two 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 plas- ma membrane remains intact until the dying cell undergoes phagocytosis, whereas in necrosis not only does the membrane become leaky, but the cell actively secretes pro- inflammatory 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 in- volving mitochondria and the other cell surface death receptors (Figure, A). In this issue of Circulation, Guo et al2 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 fac- tor 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.3 The present study focuses on binding of TNF- to TNF receptor 1. Depending on other signals and conditions in the cell, this may promote cell sur- vival, apoptosis, or a regulated form of necrosis, which in this pathway is referred to as necroptosis (Figure, B). Cell survival is stimulated by TNF-induced recruit- ment 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 al2 used multiple genetic mouse models, cultured mouse embryonic fi- broblasts, and primary cardiomyocytes to define the role of TRAF2, an E3-ubiquitin ligase, in the heart. The data show that myocardial TRAF2 levels increase signifi- cantly in response to various cardiac stresses (eg, pressure overload and myocardial infarction). Moreover, cardiomyocyte-specific deletion of TRAF2 elicits a severe di- lated cardiomyopathy even in the absence of superimposed cardiac stress. This is Death Receptor Signaling in the Heart Cell Survival, Apoptosis, and Necroptosis 2017 American Heart Association, Inc. The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. Correspondence to: Richard N. Kitsis, MD, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461 E-mail Key Words: Editorials apoptosis cell death necroptosis necrosis TNF TRAF2 by guest on August 21, 2017/Downloaded from Amgalan et al August 22, 2017 Circulation. 2017;136:743746. DOI: 10.1161/CIRCULATIONAHA.117.029566744 characterized by apoptosis (likely through complex IIb because it is sensitive to receptor interacting protein 1 kinase inhibition) and necroptosis. The rest of the ar- ticle addresses mechanism (Figure). Given its upstream role in complex I, it is not surprising that TNF receptor- associated death domain is important in cardiomyocyte apoptosis and necroptosis, as is the E3-ligase function of TRAF2. The increased plasma TNF- levels observed with cardiomyocyte-specific deletion of TRAF2 were shown to exacerbate heart failure as simultaneous deletion of TNF receptor 1 partially rescues the phenotype. Although transforming growth factor-activated kinase 1 activa- tion suffices to attenuate both apoptotic and necrop- totic events, nuclear factor-B unexpectedly appears Figure. Apoptosis and necrosis signaling. A, Overview of death receptor and mitochondrial cell death pathways. Both apoptosis and necrosis can be initiated through death receptor and mitochondrial pathways. Regardless of pathway, the defining molecular event in apoptosis is activation of cas- pases, which are a class of cysteine proteases. Caspase activation takes place in complex IIa and complex IIb in the death receptor pathway (see B) and the apoptosome in the mitochondrial pathway. Apoptosome assembly is triggered by cytochrome c, which is released through permeabilization of the outer mitochondrial membrane. The defining events in necrosis involve activation of receptor interacting proteins 1 and 3 (RIP1 and RIP3), which are kinases, in the death receptor pathway, and opening of the in- ner mitochondrial membrane permeability transition pore (PTP) in the mitochondrial pathway. BAX indicates B-cell lymphoma-2 (BCL-2)-associated X protein; BAK, BCL-2 homologous antagonist killer; BH3, BCL-2 homology domain 3; and tBid, truncated BH3-interacting domain death agonist. B, Death receptor signaling. The binding of tumor necrosis factor- (TNF-) to TNF recep- tor 1 (TNFR1) stimulates the assembly of complex I, which signals cell survival. This complex includes the adaptor protein TNF re- ceptor-associated death domain (TRADD), RIP1, and several E3-ubiquitin ligases. The addition of amino to carboxyl-linked ubiquitin chains onto RIP1 by linear ubiquitin chain assembly complex (LUBAC) provides a platform for the activation of the transcription fac- tor nuclear factor-B (NF-B). The attachment of lysine 63-linked ubiquitin chains to RIP1 by cellular inhibitor of apoptosis proteins 1 and 2 (cIAP1 and cIAP12) and tumor necrosis factor receptor-associated factor 2 (TRAF2) provides a platform for the activation of transforming growth factor-activated kinase 1 (TAK1), which in turn activates NF-B and mitogen-activated protein kinases (MAPKs). TAK1 also may be activated more directly through TRAF2-mediated ubiquitylation. Deubiquitylation of RIP1 leads to the disassembly of complex I and formation several cytoplasmic complexes. Complex IIa includes TRADD, Fas-associated death domain (FADD), and procaspase-8, the result being caspase activation and apoptosis. Complex IIb (the ripoptosome), involving RIP1, FADD, and procaspase-8, also induces apoptosis but through RIP1 phosphorylation. In addition, caspase-8 activation inhibits necroptosis by cleaving RIP1 and RIP3. If caspase-8 is inhibited, however, then complex IIc (the necrosome) may form, which signals necrop- tosis through the phosphorylation and interaction of RIP1 and RIP3. Events that mediate necroptosis downstream of RIP3 include (1) phosphorylation and recruitment of mixed lineage kinase domain-like protein (MLKL), which oligomermizes to cause plasma membrane dysfunction; (2) activation of metabolic enzymes that generate oxidative stress; and (3) activation of Ca2+-calmodulin- dependent protein kinase II- (CaMKII-), leading to opening of the inner mitochondrial membrane permeability transition pore. by guest on August 21, 2017/Downloaded from Apoptosis and Necroptosis EDITORIAL Circulation. 2017;136:743746. DOI: 10.1161/CIRCULATIONAHA.117.029566 August 22, 2017745 dispensable in this system. Both receptor interacting protein 3 and mixed lineage kinase domain-like protein were shown to be important in TNF-induced cardio- myocyte necroptosis, which is notable because mixed lineage kinase domain-like protein appears dispensable for necroptosis in some other cardiac paradigms.4 Last, in addition to the canonical induction of necroptosis re- sulting from caspase inhibition that defines the TNF- pathway, the study revealed some interesting cross-talk, whereby inhibition of necroptosis amplifies apoptosis. The major challenge not addressed by this work is the molecular nature of the connections by which TRAF2 suppresses apoptosis and necroptosis. The study does provide the important hint that the TRAF2 E3-ubiquitin ligase function is required, and clearly re- ceptor interacting protein 1 and transforming growth factor-activated kinase 1, both of which are TRAF2 substrates,5,6 are good candidates to mediate the ob- served survival effects. However, the mechanism may not be this simple because other E3-ligases in complex I can also ubiquitylate these proteins. This raises the question as to whether additional TRAF2 ubiquitylation targets are involved. Accordingly, it might be informa- tive to more broadly define the proteome modified by TRAF2, as has been accomplished for other E3-ligases.7 In addition, the possibility exists that TRAF2 may sup- press cell death indirectly through its participation in other processes, such as its recently demonstrated role in mitophagy, which is also dependent on its E3-ligase function.8 What is the relevance of these findings to the patho- genesis of heart failure? The dilated cardiomyopathy resulting from deletion of TRAF2 in cardiomyocytes un- derscores the importance of this protein in maintaining baseline cardiac structure and function. The observa- tion that TRAF2 abundance increases in response to pathological stimuli suggests that this protein also pro- tects the heart against stress. More generally, this study demonstrates that death receptor signaling results in a complex interplay of activating and inhibitory effects on adverse cardiac remodeling, thereby extending previous investigations into the role of this pathway in heart dis- ease.4,911 Can the death receptor pathway be manipulated to therapeutic advantage in heart failure using small mol- ecule drug approaches? Although activation of the sur- vival arm may not currently be in reach, a number of re- ceptor interacting protein 1 and 3 inhibitors developed for other purposes may serve to inhibit necroptosis in heart failure and, based on other data, also in isch- emic injury.3 While these approaches merit exploration, several caveats need to be considered. First, reciprocal activation of other death programs (eg, mitochondrial death pathway) (Figure A) may necessitate a combined pharmacological approach. Second, the use of cell death inhibition in any chronic setting, including heart failure, must be balanced against potential untoward effects (eg, cancer). In conclusion, this study provides an important new piece in understanding the role of cell death in heart disease. With a more complete molecular understand- ing, this pathway may be targeted therapeutically to protect the heart during the most common and lethal cardiac syndromes. ACKNOWLEDGMENTS The authors thank Dr Lorenzo Galluzzi for critical comments. SOURCES OF FUNDING Ms Amgalan received an American Heart Association Pred- octoral Fellowship (15PRE25080032). Dr Chen received an American Heart Association Scientist Development Grant (17SDG33410907). Dr Kitsis received grants from the Na- tional Institutes of Health (R01HL128071, R01HL130861, R01CA17091), Department of Defense (PR151134P1), Amer- ican Heart Association (15CSA26240000), Fondation Leducq (RA15CVD04), and support from the Dr Gerald and Myra Dorros Chair in Cardiovascular Disease, and the Wilf Family. DISCLOSURES None. AFFILIATION From Departments of Medicine (Cardiology) and Cell Biology, Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY. FOOTNOTES Circulation is available at . REFERENCES 1. Konstantinidis K, Whelan RS, Kitsis RN. Mechanisms of cell death in heart disease. Arterioscler Thromb Vasc Biol. 2012;32:15521562. doi: 10.1161/ATVBAHA.111.224915. 2. Guo X, Yin H, Li L, Chen Y, Li J, Doan J, Steinmetz R, Liu Q. Cardioprotective role of tumor necrosis factor receptor-associated factor 2 by suppressing apoptosis and necroptosis. Circulation. 2017;136:729742. doi: 10.1161/ CIRCULATIONAHA.116.026240. 3. Conrad M, Angeli JP, Vandenabeele P, Stockwell BR. Regulated necrosis: disease relevance and therapeutic opportunities. Nat Rev Drug Discov. 2016;15:348366. doi: 10.1038/nrd.2015.6. 4. Zhang T, Zhang Y, Cui M, Jin L, Wang Y, Lv F, Liu Y, Zheng W, Shang H, Zhang J, Zhang M, Wu H, Guo J, Zhang X, Hu X, Cao CM, Xiao RP. CaMKII is a RIP3 substrate mediating ischemia- and oxidative stress-induced myo- cardial necroptosis. Nat Med. 2016;22:175182. doi: 10.1038/nm.4017. 5. Zhang L, Blackwell K, Shi Z, Habelhah H. The RING domain of TRAF2 plays an essential role in the inhibition of TNFalpha-induced cell death but not in the activation of NF-kappaB. J Mol Biol. 2010;396:528539. doi: 10.1016/j.jmb.2010.01.008. 6. Fan Y, Yu Y, Shi Y, Sun W, Xie M, Ge N, Mao R, Chang A, Xu G, Schneider MD, Zhang H, Fu S, Qin J, Yang J. Lysine 63-linked polyubiquitination by guest on August 21, 2017/Downloaded from Amgalan et al August 22, 2017 Circulation. 2017;136:743746. DOI: 10.1161/CIRCULATIONAHA.117.029566746 of TAK1 at lysine 158 is required for tumor necrosis factor alpha- and interleukin-1beta-induced IKK/NF-kappaB and JNK/AP-1 activation. J Biol Chem. 2010;285:53475360. doi: 10.1074/jbc.M109.076976. 7. Sarraf SA, Raman M, Guarani-Pereira V, Sowa ME, Huttlin EL, Gygi SP, Harper JW. Landscape of the PARKIN-dependent ubiquitylome in re- sponse to mitochondrial depolarization. Nature. 2013;496:372376. doi: 10.1038/nature12043. 8. Yang KC, Ma X, Liu H, Murphy J, Barger PM, Mann DL, Diwan A. Tumor necrosis factor receptor-associated factor 2 mediates mitochondrial au- tophagy. Circ Heart Fail. 2015;8:175187. doi: 10.1161/CIRCHEARTFAIL- URE.114.001635. 9. Burchfield JS, Dong JW, Sakata Y, Gao F, Tzeng HP, Topkara VK, Entman ML, Sivasubramanian N, Mann DL. The cytoprotective effects of tumor ne- crosis factor are conveyed through tumor necrosis factor receptor-associ- ated factor 2 in the heart. Circ Heart Fail. 2010;3:157164. doi: 10.1161/ CIRCHEARTFAILURE.109.899732. 10. Luedde M, Lutz M, Carter N, Sosna J, Jacoby C, Vucur M, Gautheron J, Roderburg C, Borg N, Reisinger F, Hippe HJ, Linkermann A, Wolf MJ, Rose- John S, Lllmann-Rauch R, Adam D, Flgel U, Heikenwalder M, Luedde T, Frey N. RIP3, a kinase promoting necroptotic cell death, mediates adverse remodelling after myocardial infarction. Cardiovasc Res. 2014;103:206 216. doi: 10.1093/cvr/cvu146. 11. Lee P, Sa

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