Disruption of RIP1-FADD Complexes by MicroRNA-103/107 Provokes Necrotic Cardiac Cell Death.

Abstract

The adult myocardium has a limited capacity for de novo regeneration.1 Hence, the loss of functional cardiac myocytes by apoptosis and necrosis is postulated as a central underlying mechanism for ventricular remodeling and heart failure. Although multiple signaling pathways have been proposed, a cogent explanation for how these highly conserved and intricate cell death pathways are regulated in the ischemic myocardium has not been resolved. Given that cardiac function is regulated by the number of viable cardiac myocytes, 1 unifying theme toward the ultimate therapeutic goal in preventing heart failure is to preserve the number of existing cardiac myocytes by suppressing cell death. Article, see p 352 In the early days of understanding mechanisms of cell death signaling, much enthusiasm surrounded apoptosis in the pathogenesis of many human diseases, because at that time apoptosis was thought to be the only mode of cell death that was programmed or genetically regulated. Because necrosis has been viewed historically as an accidental or an unregulated form of death, it was largely overlooked or even ignored as a mode of cell death that could be manipulated therapeutically.2,3 During the past several years a greater appreciation and detailed understanding of the molecular signaling pathways that underlie apoptotic and necrotic signaling pathways, together with improved biochemical techniques, have sparked an insurgent interest in necrotic cell death with the resultant revelation that necrosis is indeed a regulated program. In fact, the concept that necrotic death is genetically programmed has tremendous implications for understanding the pathogenesis of cardiac diseases that were previously unexplored. Little is known of the signaling pathways that govern necrotic death in the heart. Receptor interacting protein 1 (RIP1), a member of serine-threonine protein kinase family of RIPs, has been identified to play a central role in innate immunity, adaptive immunity, …