Gender-based differences in mechanisms of protection in myocardial ischemia–reperfusion injury

Pre-menopausal women have reduced risk for cardiovascular disease, and cardiovascular disease rises after menopause. Studies in animal models have also suggested that females have reduced injury following ischemia and reperfusion (I/R). However, a large clinical trial, the Women's Health Initiative, found an increase in cardiovascular incidents in women on hormone replacement therapy. Taken together, these data suggest that we need a better understanding regarding the mechanisms for the protection observed in the animal studies. In some studies, particularly in the rat, females show less I/R injury; however, in many animal studies no gender difference in I/R injury is observed. Under conditions where calcium is elevated or contractility is increased just prior to ischemia, females have been reported to have less I/R injury than males. Also, estrogen administration has been shown to reduce I/R injury. The protection observed under conditions of increased contractility has been shown to involve an increase in nitric oxide signaling leading to S-nitrosylation of the L-type calcium channel, which reduces calcium loading during ischemia and early reperfusion thereby reducing I/R injury. Estrogen binding to nuclear estrogen receptors results in altered expression of a number of cardioprotective genes such as nitric oxide synthase and heat shock proteins. Estrogen also alters a number of genes involved in metabolism such as lipoprotein lipase, prostaglandin D2 synthase, and peroxisome proliferator activated receptor gamma coactivator 1 alpha (PGC-1-alpha). The effects of these alterations in gene expression may depend on the context of other hormonal stimuli and gene expression as well as physiological stimuli. Furthermore, addition of estrogen has acute non-genomic responses that involve activation of the phosphatidylinositol 3-kinase (PI 3-kinase) pathway, which has been shown to be protective, at least when activated for short durations. This review will summarize the data showing protection in females in animal studies and will summarize the data on possible mechanisms of cardioprotection in females.