Protein Kinase C Beta II (PKC ßII) Peptide Inhibitor Exerts Cardioprotective Effects in Myocardial Ischemia/Reperfusion Injury

Coronary heart disease is the leading cause of death worldwide, and is primarily attributable to the detrimental effects of tissue infarct after an ischemic insult. The most effective therapeutic intervention for reducing infarct size associated with myocardial ischemia injury is timely and effective reperfusion of blood flow back to the ischemic heart tissue. However, the reperfusion of blood itself can induce additional cardiomyocyte death that can account for up to 50% of the final infarction size. Currently, there are no effective clinical pharmacologic treatments to limit myocardial ischemia/reperfusion (MI/R) injury in heart attack patients [1]. Reperfusion injury is initiated by decreased endothelialderived nitric oxide (NO) which occurs within 5 min of reperfusion [2], and may in part be explained by PKC II mediated activation of NADPH oxidase, which occurs upon cytokine release during MI/R [3]. PKC II activity is increased in animal models of MI/R and known to exacerbate tissue injury [4,5]. PKC II is known to increase NADPH oxidase activity in leukocytes, endothelial cells and cardiac myocytes via phox47 phosphorylation, and decrease endothelial NO synthase (eNOS) activity via phosphorylation of Thr 495 [6-8]. NADPH oxidase produces superoxide (SO) and quenches endothelial derived NO in cardiac endothelial cells. Moreover, PKC II phosphorylation of p66Shc at Ser 36 leads to increased mitochondrial reactive active oxygen species (ROS) production, opening of the mitochondrial permeability transition pore (MPTP), and pro-apoptotic factors leading to cell death and increased infarct size [9] (Figure 1 left). Therefore, using a pharmacologic agent that inhibits the rapid release of PKC II mediated ROS, would attenuate endothelial dysfunction and downstream pro-