Potential mechanisms of heat shock protein 90 inhibitors in rat neonatal ventricular myocytes

Heat shock proteins (hsps) have been shown to protect against ischemic injury in the heart. A pharmacological means of inducing hsps to confer cardioprotection may be found in compounds known as hsp90 inhibitors. These inhibitors cause the heat shock factor 1 (HSF1) to be released from the hsp90 complex as well as hsp90 client protein degradation to occur. We have investigated a group of geldanamycin analogues in rat neonatal ventricular myocytes in vitro . We have found that these compounds do induce a heat shock response as indicated by an upregulation of hsps. We also tested these compounds for cardioprotection after simulated ischemia and found that only some of the hsp90 inhibitors confer protection. Upon this finding, we further examined the differences between the hsp90 inhibitors by studying their effects on HSF1 activation and its binding to the heat shock element. We also looked at the level of hsp90 client protein degradation as examined by ErbB2 protein levels. The results of these studies revealed that cardioprotection occurred when there was not only HSF1 activation and upregulation of hsps, but also with ErbB2 degradation. This led us to question whether the cardioprotection is due solely to ErbB2 degradation. Therefore, we blocked the induction of hsps through use of an HSF1 inhibitor. HSF1 inhibition led to a decrease in cardioprotection. Therefore, these results indicate that cardioprotection by hsp90 inhibitors is achieved both through HSF1 activation and client protein degradation. This research is funded by the NHLBI.