Mechanisms of cardioprotection by heat shock protein 90 inhibitors

Cardiovascular disease (CVD) is the leading cause of death in the United States among both males and females of all ages. Heat shock proteins are molecular chaperones found in all organisms and are upregulated in response to stressful stimuli including myocardial ischemia. Overexpression studies have shown that some hsps are cardioprotective in both in vitro and in vivo. Therefore, a pharmacological means of inducing hsps could be therapeutically beneficial. Naturally occurring compounds known as benzoquinone ansamycins have been found to induce hsps. Furthermore, these compounds have also been found to confer cardioprotection after simulated ischemia. The benzoquinone ansamycins are hsp90 inhibitors. It was found that the inhibition of hsp90 led to the release and activation of HSF1 resulting in the upregulation of hsps. Hsp90 inhibition also results in hsp90 client protein degradation. Many of the client proteins are involved in cell regulation, which has made hsp90 inhibitors a therapeutic target for cancer research. Unfortunately, the benzoquinone ansamycins proved too toxic for clinical use. Thus, derivatives of the benzoquinone ansamycins and synthetic small molecule modulators have been synthesized to overcome the toxic effects of the naturally occurring hsp90 inhibitors. We have tested a group of novel hsp90 inhibitors and found that they are well tolerated in myocytes. These hsp90 inhibitors were also found to induce hsps and some were able to confer cardioprotection against simulated ischemia. To further define the mechanisms of cardioprotection by the hsp90 inhibitors, the compounds were compared for their ability to activate HSF1 and degrade client proteins. The experiments revealed that there was a difference in client protein degradation between the compounds that protect and those that did not. HSF1 inhibitors were used to define the role that hsp induction plays in cardioprotection. The results showed that inhibition of hsp induction significantly reduced cardioprotection by the hsp90 inhibitors. While client protein degradation may have a role in cardioprotection elicited by the hsp90 inhibitors, the results indicate that hsp induction is essential.