Heat-shock factor-1, steroid hormones, and regulation of heat-shock protein expression in the heart

Heat-shock proteins (HSPs) are an important family of endogenous, protectiv e proteins. Overexpression of HSPs is protective against cardiac injury. Pr eviously, we observed that dexamethasone activated heat-shock factor-1 (HSF -1) and induced a 60% increase in HSP72 in adult cardiac myocytes. The mech anism responsible for this effect of dexamethasone is unknown. Because HSP9 0 is known to bind the intracellular hormone receptors, we postulated that the interaction between HSP90, the receptors, and HSF was an important elem ent in activation of HSF-1 by hormones. We hypothesized that there is an eq uilibrium between HSP90 and the various receptors/enzymes that it binds and that alteration in levels of certain hormones will alter the intracellular distribution of HSP90 and activate HSF-1. We report that, in adult cardiac myocytes, HSF-1 coimmunoprecipitates with HSP90. HSP90 redistributes in ca rdiac myocytes after treatment with 17 beta -estradiol or progesterone. Est rogen and progesterone activate HSF-1 in adult male isolated cardiac myocyt es, and this is followed by an increase in HSP72 protein. Testosterone had no effect on HSP levels; however, no androgen receptor was found in cardiac myocytes; therefore, testosterone would not be expected to effect binding of HSP90 to HSF. Geldanamycin, which inactivates HSP90 and prevents it from binding to receptors, activates HSF-1 and stimulates HSP72 synthesis. Acti vation of HSF-1 by steroid hormones, resulting from a change in the interac tion of HSP90 and HSF-1, represents a novel pathway for regulating expressi on of HSPs. These findings may explain some of the gender differences in ca rdiovascular disease.