Death Receptor Signaling in the Heart: Cell Survival, Apoptosis, and Necroptosis.

Abstract

Article, see p 729 Research 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.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 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 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 factor 2 (TRAF2), a protein in this pathway, results in dilated cardiomyopathy through unleashing apoptotic and necrotic cardiomyocyte death. 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 caspases, which are a class of cysteine proteases. Caspase activation takes place …