Gender-based Differences in Cardiac Calcium Regulation

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The disparity in the prevalence of heart disease in males and premenopausal females is profound, and studies to determine the mechanism of protection in females have been inconclusive. Isolated hearts and ventricular myocytes from male and female mice will be used to explore gender-based differences in cardiac function, calcium homeostasis, and recovery from ischemia/reperfusion (IR) injury. Two interrelated hypotheses will be tested: 1. Basic aspects of cardiac contractile function differ between male and female isolated hearts. These differences in the regulation of contractility can be explained, at least in part, by gender-specific differences in cellular calcium homeostasis. 2. Male and female hearts respond differently to ischemia/reperfusion injury. The differences in recovery from ischemia can be explained by different levels of calcium overload during early reperfusion. Gender-specific differences in Ca homeostasis also underlie the divergent response to IR injury. The specific aims of this research are: 1. Tests of hypothesis 1: A. Isometric force measurements will be made in hearts isolated from male and female mice. Calcium dose-response curves will be determined in male and female hearts. B. Individual myocytes isolated from male and female hearts will be loaded with the Ca-sensitive fluorescent dye indo- 1, and twitch contractions and intracellular calcium transients will be measured at different stimulation rates and bath [Ca]. These experiments will determine if myocyte contractility and/or calcium handling differs between male and female hearts. 2. Tests of hypothesis 2: A. Isometric force measurements will be made in isolated hearts before exposure to global ischemia and after global ischemia followed by reperfusion. B. Ca transients and twitch contractions will be compared in indo-1-loaded myocytes isolated from male and female hearts before and after simulated IR injury. These studies will provide new insights into gender- based differences in cardiac function and dysfunction.