Mechanisms involved in male-female differences in cardioprotection

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Although gender disparities in cardiac disease are recognized, the mechanisms through which pre-menopausal females are protected have not been fully elucidated. Cardiac disease incidence in females increases post-menopause, suggesting a role for estrogen in pre-menopausal cardioprotection. However, clinical trials found no beneficial cardiovascular outcomes from hormone replacement therapy, indicating a better mechanistic understanding is needed. Thus the goal of this study is to understand the mechanism responsible for the male-female differences in ischemia-reperfusion injury, cardioprotection and hypertrophy. We reported previously that under conditions of calcium overload, as occurs with overexpression of plasma membrane sodium-calcium exchanger, loss of phospholamban or overexpression of beta-adrenergic receptor, females have less I/R injury. We developed methods to measure mitochondrial calcium during I/R to test whether there are sex differences in mitochondrial calcium uptake during I/R. With our new method to measure mitochondrial calcium during I/R we are tested whether there are sex differences in mitochondrial calcium uptake during I/R. Our preliminary studies show that during ischemia female accumulate less mitochondrial calcium than males. We are testing to see whether these differences are due to alterations in mitochondrial calcium uptake or efflux mechanisms.