PKCβ modulates ischemia-reperfusion injury in the heart

Protein kinase C-beta II (PKC beta II) is an important modulator of cellular stress responses. To test the hypothesis that PKC beta II modulates the response to myocardial ischemia-reperfusion (I/R) injury, we subjected mice to occlusion and reperfusion of the left anterior descending coronary artery. Homozygous PKC beta-null (PKC beta(-/-)) and wildtype mice fed the PKC beta inhibitor ruboxistaurin displayed significantly decreased infarct size and enhanced recovery of left ventricular (LV) function and reduced markers of cellular necrosis and serum creatine phosphokinase and lactate dehydrogenase levels compared with wild-type or vehicle-treated animals after 30 min of ischemia followed by 48 h of reperfusion. Our studies revealed that membrane translocation of PKC beta II in LV tissue was sustained after I/R and that gene deletion or pharmacological blockade of PKC beta protected ischemic myocardium. Homozygous deletion of PKC beta significantly diminished phosphorylation of c-Jun NH2-terminal mitogen-activated protein kinase and expression of activated caspase-3 in LV tissue of mice subjected to I/R. These data implicate PKC beta in I/R-mediated myocardial injury, at least in part via phosphorylation of JNK, and suggest that blockade of PKC beta may represent a potent strategy to protect the vulnerable myocardium.