Novel functional role of heat shock protein 90 in protein kinase C-mediated ischemic postconditioning

BackgroundPrevious studies have shown that heat shock protein 90 (HSP90) plays a vital role in ischemic preconditioning. The present study was designed to explore whether HSP90 might be responsible for cardioprotection in ischemic postconditioning (PostC).Materials and methodsRat hearts underwent 30 min of regional ischemia and 2 h of reperfusion in situ, and PostC was effected with three cycles of 30-s reperfusion and 30-s coronary artery occlusion at the end of ischemia. Ninety rats were randomized into five groups: sham; ischemia–reperfusion (I/R); PostC; 1 mg/kg HSP90 inhibitor geldanamycin (GA) plus PostC (PostC + GA1); and 5 mg/kg GA plus PostC (PostC + GA5). The GA was administered 10 min before reperfusion.ResultsCompared with the I/R group, the PostC group exhibited lower infarct size (46.7 ± 3.0% versus 27.4 ± 4.0%, respectively), release of lactate dehydrogenase and creatine kinase-MB (2252.6 ± 350.8 versus 1713.7 ± 202.4 IU/L, 2804.3 ± 315.7 versus 1846.2 ± 238.0 IU/L, respectively), cardiomyocyte apoptosis (48.4 ± 5.6% versus 27.6 ± 3.8%, respectively), and mitochondrial damage. These beneficial effects were accompanied by an increase in mitochondrial Bcl-2 levels and a decrease in Bax levels. In addition, mitochondrial protein kinase Cepsilon (PKCepsilon) was relatively low in the I/R group but significantly higher in the PostC group, whereas cytosolic PKCepsilon was relatively high in the I/R group but significantly lower in the PostC group, suggesting the translocation of PKCepsilon from cytosol to mitochondria during PostC. However, blocking HSP90 function with GA inhibited the protection of PostC and PKCepsilon mitochondrial translocation.ConclusionsHSP90 is critical in PostC-induced cardioprotection, and its activity might be linked to mitochondrial targeting of PKCepsilon, the activation of which results in upregulation of its target gene, Bcl-2, and the inhibition of proapoptotic Bax in mitochondria.