Fundamental Mechanisms of Regulated Cell Death and Implications for Heart Disease
Top Cited Papers
- 1 October 2019
- journal article
- review article
- Published by American Physiological Society in Physiological Reviews
- Vol. 99 (4), 1765-1817
- https://doi.org/10.1152/physrev.00022.2018
Abstract
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.Keywords
Funding Information
- HHS | National Institutes of Health (NIH) (R01HL127339, R15HL135726, R01HL128071, R01HL130861)
- HHS | National Institutes of Health (NIH) (R01HL116507, R01HL128071, R01HL130861)
- HHS | National Institutes of Health (NIH) (R01HL138475)
- U.S. Department of Defense (DOD) (PR151134P1)
- American Heart Association (AHA) (15CSA26240000, 15PRE25080032)
- American Heart Association (AHA) (18SRG34280018)
- Fondation Leducq
- Deutsche Forschungsgemeinschaft (DFG) (EXC 306)
- Pfizer
- Novartis
- Else Kröner-Fresenius-Stiftung (Else Kroner-Fresenius Foundation)
This publication has 503 references indexed in Scilit:
- Survival Function of the FADD-CASPASE-8-cFLIPL ComplexCell Reports, 2012
- Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell DeathCell, 2012
- Sphingolipid Metabolism Cooperates with BAK and BAX to Promote the Mitochondrial Pathway of ApoptosisCell, 2012
- Mixed Lineage Kinase Domain-like Protein Mediates Necrosis Signaling Downstream of RIP3 KinaseCell, 2012
- Bcl-xL Retrotranslocates Bax from the Mitochondria into the CytosolCell, 2011
- Phosphorylation-Driven Assembly of the RIP1-RIP3 Complex Regulates Programmed Necrosis and Virus-Induced InflammationCell, 2009
- Receptor Interacting Protein Kinase-3 Determines Cellular Necrotic Response to TNF-αCell, 2009
- Identification of a Molecular Signaling Network that Regulates a Cellular Necrotic Cell Death PathwayCell, 2008
- Transcriptional control by PARP-1: chromatin modulation, enhancer-binding, coregulation, and insulationCurrent Opinion in Cell Biology, 2008
- Overexpression of IAP-2 attenuates apoptosis and protects against myocardial ischemia/reperfusion injury in transgenic miceBiochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2007