Mechanisms involved in male-female differences in cardioprotection

National Heart, Lung, And Blood Institute

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Abstract

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 are developing 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 testing whether there are sex differences in mitochondrial calcium uptake during I/R. Heart failure preceded by hypertrophy is a leading cause of death, and sex differences in hypertrophy are well known, although the basis for these sex differences is poorly understood. We used a systems biology approach to investigate mechanisms underlying sex differences in cardiac hypertrophy. Male and female mice were treated for 2 and 3 weeks with angiotensin II to induce hypertrophy. Sex differences in cardiac hypertrophy were apparent after 3 weeks of treatment. RNA sequencing was performed on hearts, and sex differences in mRNA expression at baseline and following hypertrophy were observed, as well as within-sex differences between baseline and hypertrophy. Sex differences in mRNA were substantial at baseline and reduced somewhat with hypertrophy, as the mRNA differences induced by hypertrophy tended to overwhelm the sex differences. We performed an integrative analysis to identify mRNA networks that were differentially regulated in the 2 sexes by hypertrophy and obtained a network centered on PPARa (peroxisome proliferator-activated receptor a). Mouse experiments further showed that acute inhibition of PPARa blocked sex differences in the development of hypertrophy. The data in this study suggest that PPARa is involved in the sex-dimorphic regulation of cardiac hypertrophy. We have developed a cardiac specific PPAR-alphaknockout mouse that we are currently using to test the hypothesis that PPAR-alpha signaling plays a role in the sex dimorphic regulation of cardiac hypertrophy.