Regulation of mitochondrial function by deltaPKC during cardiac ischemia/reperfusion

Acute myocardial infarction (AMI) is a leading cause of death in the United States. While the mechanical or pharmacological restoration of blood flow prevents further ischemic injury, reperfusion of ischemic myocardium has also been shown to have deleterious effects on cardiac function. The cardiac dysfunction seen during reperfusion is thought to proceed through an apoptosic pathway of cell death. The reperfusion of ischemic myocardium is also associated with an increase in mitochondrial free radical generation. The generation of reactive oxygen species (ROS) by the mitochondria results in the oxidation of cellular antioxidants which can lead to a condition of oxidative stress within the cardiomyocyte. Oxidative stress has been shown to result in the induction of apoptosis in isolated cardiomyocytes. Mechanisms linking the generation of mitochondrial ROS to the declines in cardiac function seen during reperfusion have yet to be elucidated.; deltaPKC is a cytosolic serine/threonine kinase that is activated during conditions of oxidative stress. ROS dependent activation of deltaPKC in non-cardiac cell types results in translocation to the mitochondria where it is involved in the initiation of apoptosis. Furthermore, inhibition of deltaPKC during cardiac reperfusion has been shown to be cardioprotective suggesting a possible role of deltaPKC in the induction of apoptosis. Therefore, we hypothesize that activation of deltaPKC by free radicals generated during the reperfusion of ischemic myocardium results in translocation of deltaPKC to the mitochondria resulting in disruption of mitochondrial function and initiation of apoptosis.; The results of this project demonstrate that deltaPKC translocates to the mitochondria exclusively during the early stages of reperfusion. In addition, continued reperfusion results in sustained translocation of deltaPKC to the mitochondria, cytochrome-c release and induction of apoptosis. This is accompanied by a decrement in mitochondrial function and a maintenance of PDH in an inactive state. These results demonstrate that translocation of deltaPKC to the mitochondria has time dependent effects on mitochondrial function ultimately culminating to apoptosis of the cardiomyocyte. It is apparent that deltaPKC has a diverse set of effects on mitochondrial and cardiac function suggesting a complex mode of regulation. A mechanism of differential activation of deltaPKC may explain the different roles of deltaPKC during cardiac reperfusion.