Myristoylated Protein Kinase C Epsilon Peptide Inhibitor Exerts Cardioprotective Effects in Rat and Porcine Myocardial Ischemia/Reperfusion: A Translational Research Study

摘要

Following an acute myocardial infarction, the rapid restoration of blood flow to the ischemic myocardium is the most effective method of limiting infarct size and improving patient outcomes. However, reperfusion leads to the loss of cardiomyocytes that were viable during the ischemic episode and is referred to as ischemia/reperfusion (I/R) injury [1]. This restoration of blood flow is known to result in the overproduction of reactive oxygen species (ROS), as incoming oxygen reacts with the damaged mitochondrial respiratory chain to produce superoxide that in turn leads to the enzymatic uncoupling of endothelial nitric oxide synthase (eNOS) and the production of more ROS and reduced nitric oxide (NO) bioavailability [2]. The reduction in NO has been shown to reduce the coupling efficiency of O2 consumption and ATP synthesis in cardiac mitochondria, presumably leading to further ROS production during in I/R [3]. It is well established that protein kinase C epsilon (PKCe) activity can stimulate eNOS activity. During I/R, PKCs activity is activated via stimulation of cytokine receptors and enhances uncoupled eNOS activity [4]. We hypothesized that limiting PKCe activity during I/R using a cell permeable myristoylated PKCs peptide inhibitor (PKCe-) should limit ROS production in part by attenuating uncoupled eNOS activity and thereby improve heart function and reduce infarct size.