Multiple Cell Death Programs Contribute to Myocardial Infarction

HomeCirculation ResearchVol. 129, No. 3Multiple Cell Death Programs Contribute to Myocardial Infarction Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessEditorialPDF/EPUBMultiple Cell Death Programs Contribute to Myocardial Infarction Xiaotong F. Jia, Felix G. Liang and Richard N. Kitsis Xiaotong F. JiaXiaotong F. Jia Cell Biology (X.F.J., F.G.L., R.N.K.), Albert Einstein College of Medicine, Bronx, NY. Wilf Family Cardiovascular Research Institute (X.F.J., F.G.L., R.N.K.), Albert Einstein College of Medicine, Bronx, NY. , Felix G. LiangFelix G. Liang Cell Biology (X.F.J., F.G.L., R.N.K.), Albert Einstein College of Medicine, Bronx, NY. Wilf Family Cardiovascular Research Institute (X.F.J., F.G.L., R.N.K.), Albert Einstein College of Medicine, Bronx, NY. and Richard N. KitsisRichard N. Kitsis Correspondence to: Richard N. Kitsis, MD, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461. Email E-mail Address: [email protected] https://orcid.org/0000-0003-1395-9694 Departments of Medicine (Cardiology) (R.N.K.), Albert Einstein College of Medicine, Bronx, NY. Cell Biology (X.F.J., F.G.L., R.N.K.), Albert Einstein College of Medicine, Bronx, NY. Wilf Family Cardiovascular Research Institute (X.F.J., F.G.L., R.N.K.), Albert Einstein College of Medicine, Bronx, NY. Originally published22 Jul 2021https://doi.org/10.1161/CIRCRESAHA.121.319584Circulation Research. 2021;129:397–399This article is a commentary on the followingGSDMD-Mediated Cardiomyocyte Pyroptosis Promotes Myocardial I/R InjuryArticle, see p 383Cell death has become more complicated. From the mid-1980s to almost the turn of the millennium, apoptosis was the only recognized form of regulated cell death. But, presently, at least 10 other mechanistically distinct cell death programs have been defined.1 While some of these entities may coalesce with deeper understanding, the take-home message is clear: cells can die through multiple regulated paradigms. This raises important fundamental questions: (1) Why are there so many cell death programs? (2) What are their evolutionary relationships? (3) How do they interconnect at the molecular level? (4) What determinants direct a stressed or damaged cell toward one death program versus another? The absence of a unified field theory—to borrow a concept from physics—that unites disparate cell death programs into a coherent whole is a major gap in our understanding.Work over the past ≈30 years has demonstrated that regulated cell death contributes to the pathogenesis of heart disease, including myocardial infarction (MI) and heart failure.2 The importance of cell death depends on the disease. For example, in heart failure with reduced ejection fraction, the slow attrition of cardiomyocytes through regulated cell death programs is one of multiple mechanisms leading to adverse cardiac remodeling and systolic dysfunction.3 In contrast, in MI, the defining cardiac event is the acute deaths of large numbers of myocardial cells, and the size of the resulting infarct is the major determinant of subsequent heart failure and mortality. Studies in mice suggest that much of the cell death in reperfused MI (MI/R) occurs through regulated cell death programs. What remains unclear is exactly which programs and how they interrelate. Genetic loss of function studies in the 1990s demonstrated that both the mitochondrial4,5 and death receptor6 apoptosis pathways contribute to cardiac damage during MI/R. Subsequent work, however, has implicated other forms of cell death, including mitochondrial-dependent necrosis (mediated by opening of the mitochondrial permeability transition pore)7,8; necroptosis (a form of necrosis mediated by RIPK3 [receptor interacting kinase 3] and MLKL [mixed lineage kinase domain-like] and often involving death receptors and RIPK1)9; ferroptosis (an iron-dependent form of cell death defined by lipid peroxidation of intracellular membranes)10,11; autosis (a specific form of autophagy-dependent cell death)12; and pyroptosis described below. In this issue of Circulation Research, Shi et al13 provide both the first evidence that cardiomyocytes themselves undergo pyroptosis during MI/R and that GSDMD (gasdermins D) is critical.Pyroptosis is a form of necrosis, a collection of cell death programs defined morphologically by early loss of plasma membrane integrity. In the case of pyroptosis, this occurs through the creation of huge pores (>200 angstroms) by GSDMD or GSDME (gasdermin E; also known as DFNA5 [deafness-associated tumor suppressor]14,15; Figure) Gasdermins are activated by cleavage, which relieves autoinhibition of the death-promoting N terminus by the C terminus. Cleavage is mediated by caspases, which are cysteine proteases that cut following aspartic acid residues. However, in the case of GSDMD, the relevant caspases are not the ones involved with apoptosis, but rather inflammatory caspases-1, 4, 5 in human and 1 and 11 in mouse. Procaspase-1 is activated through the canonical pathway within inflammasomes, which are multi-protein cytosolic complexes whose assembly is triggered by diverse inflammatory and innate immune stimuli. In contrast, procaspases-4, 5, and 11 are activated through a noncanonical pathway involving the binding of lipopolysaccharide. GSDME, however, is activated by apoptotic caspases-3 and by granzyme B, a serine protease transferred from certain immune cells to kill their target cells. The creation of plasma membrane pores during pyroptosis allows the release of GSDMs into the extracellular space. Interestingly, however, GSDMs do not damage plasma membranes of neighboring cells because of critical differences in outer versus inner leaflet phospholipids. However, mature forms of interleukin 1β and interleukin 18, also generated through caspase cleavage, are released and engender an intense inflammatory response.Download figureDownload PowerPointFigure. Canonical and noncanonical pathways activate gasdermins to induce pyroptosis. Pathway described in text. ALR indicates absent in melanoma 2 (AIM2)-like receptor; ASC, apoptosis-associated speck-like protein containing a caspase activation and recruitment domain; DAMPs, damage-associated molecular patterns; GSDMD, gasdermin D; GSDME, gasdermin E; IL-18, interleukin 18; IL-1β, interleukin 1β; LPS, lipopolysaccharide; NLR, nucleotide-binding domain-like receptors; OxPL, oxidized phospholipids; and PAMPs, pathogen-associated molecular patterns.Previous research has suggested a role for pyroptosis in MI/R. Global deletion of inflammasome pathway components, ASC (apoptosis-associated speck-like protein containing a caspase activation and recruitment domain) and procaspase-1, limits infarct size.16 However, as the above perturbations are not cell type specific, these observations do not address whether pyroptosis occurs in cardiomyocytes. Although cardiomyocytes can assemble inflammasomes, they do so sluggishly compared to other cell types. Moreover, the cardioprotective effects of ASC knockout are attributable to its loss in cardiac fibroblasts and infiltrating inflammatory cells. These data raise questions about whether cardiomyocyte pyroptosis really occurs.The work reported by Shi et al addresses this issue and provides critical details concerning pyroptosis signaling in cardiomyocytes. The authors show that GSDMD, but not GSDME, is activated during hypoxia/reoxygenation in adult and neonatal mouse cardiomyocytes and during MI/R in mice in vivo. Moreover, cardiomyocyte death and infarct size are significantly attenuated by cardiomyocyte-specific deletion of GSDMD. GSDMD activation in these models is mediated by caspase-11, rather than caspase-1, explaining how cardiomyocyte pyroptosis can take place in the absence of significant inflammasome assembly. Furthermore, oxidative stress, an important component of reperfusion, contributes to activation of this pathway. Finally, GSDMD was shown to be released into the circulation of patients undergoing percutaneous coronary intervention in the context of ST-segment–elevation MI, but not stable coronary artery disease, suggesting that this protein might provide an additional diagnostic marker.The most important conclusion from this work is that GSDMD-mediated cardiomyocyte pyroptosis contributes to heart damage during MI/R. An important unanswered issue is the upstream signaling that connects MI/R with activation of this pathway. We know that oxidative stress plays a role in the activation of caspase-11, but the precise mechanism, as well as other activating inputs, remains to be delineated.The biggest unresolved issue, however, is how the multiple cell death programs implicated in MI/R fit together to generate the infarct. This question is not limited to MI/R as multiple cell death programs also appear to operate in other pathological situations, such as stroke and immunogenic cancer cell death. One wonders whether different death programs operate simultaneously in different cardiomyocytes? Or, whether these programs are temporarily separated? Or, perhaps most intriguing, whether the molecular pathways involved in each program integrate into a unified response? An understanding of these issues has important therapeutic implications.AcknowledgmentsWe thank Drs Judy Lieberman and Antonio Abbate for critical comments.Sources of FundingR.N. Kitsis is supported by the National Institutes of Health (NIH) grants R01HL138475 and R21CA235139, DOD grant PR191593, Fondation Leducq grant RA15CVD04, and Dr Gerald and Myra Dorros Chair in Cardiovascular Disease. F.G. Liang is supported by NIH grant T32HL144456. We thank the Wilf Family for their generous support.Disclosures R.N. Kitsis is cofounder of ASPIDA Therapeutics, Inc. The other authors report no conflicts.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Sources of Funding and Disclosures, see page 399.Correspondence to: Richard N. Kitsis, MD, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461. Email richard.[email protected]orgReferences1. Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam D, Agostinis P, Alnemri ES, Altucci L, Amelio I, Andrews DW, et al.. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.Cell Death Differ. 2018; 25:486–541. doi: 10.1038/s41418-017-0012-4CrossrefMedlineGoogle Scholar2. Del Re DP, Amgalan D, Linkermann A, Liu Q, Kitsis RN. Fundamental mechanisms of regulated cell death and implications for Heart Disease.Physiol Rev. 2019; 99:1765–1817. doi: 10.1152/physrev.00022.2018CrossrefMedlineGoogle Scholar3. 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Circulation Research. 2021;129:383-396 July 23, 2021Vol 129, Issue 3Article InformationMetrics © 2021 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.121.319584PMID: 34292784 Originally publishedJuly 22, 2021 KeywordsEditorialscell deathmyocardial infarctionapoptosisheart failurepyroptosisPDF download Advertisement