Molecular regulators of cardiac myocyte apoptosis during ischemia -reperfusion

Abstract

Ischemic heart disease is a major cause of death in the US. Although apoptosis have been implicated in the pathogenesis of ischemia/reperfusion injury in the heart, the critical regulators involved are unclear. Therefore, our objectives were to test the function of specific apoptotic regulators in vivo and in vitro during ischemia/reperfusion. These regulators include Fas, a death receptor; Bid, a possible link between death receptors and mitochondrial pathways; ARC, a muscle specific apoptosis inhibitor implicated in the regulation of both pathways.;The Fas pathway is functional in cardiomyocytes as demonstrated by apoptosis in cardiomyocytes transduced with a FasL adenovirus in vitro and in vivo. Moreover, Fas is critical for ischemia/reperfusion injury as the infarct size and apoptotic myocytes are significantly reduced in lpr mice (∼63% and 63.8%, respectively) as compared to the control.;Bid is also critical in cardiomyocyte apoptosis during ischemia/reperfusion injury. Bid is activated 1.5 hours after reperfusion, in vivo. bid-/- mice subjected to ischemia/reperfusion exhibited a marked reduction (53%) in infarct size and apoptotic events (cytochrome c release and caspase-9 and -3 activation). In addition, post-ischemic cardiac function was improved significantly in bid-/- mice. This further indicated the importance of Bid in cardiac injury and dysfunction following ischemia/reperfusion.;ARC-overexpressing-neonatal cardiomyocytes subjected to simulated ischemia exhibited decreased apoptosis with decreased cytochrome c release and caspase-9 activation. To test the role of ARC in cardiac injury during ischemia-reperfusion, transgenic (tg) mice with cardiac-specific overexpression of ARC were generated. Unexpectedly, ARC overexpression resulted in very few ARC tg live births relative to normal wild-type mice. Moreover, hearts of ARC tg mice exhibited hypertrophy and myofiber degeneration. In summary, although ARC protects neonatal rat cardiomyocytes from apoptosis, too much ARC might interfere with cardiac development.;These studies revealed the importance of the Fas pathway and Bid during ischemia/reperfusion, and began to delineate the role of the anti-apoptosic regulator, ARC, in cardiac myocytes. Taken together, they illustrate the critical role of the death receptor pathway in ischemia reperfusion injury. Moreover, they suggest that cardiomyocyte apoptosis is a critical process in the pathogenesis of ischemia reperfusion injury.