Gender-based Differences in Cardiac Calcium Regulation

男性和绝经前女性心脏病患病率的差异很大，确定女性保护机制的研究尚未得出结论。雄性和雌性小鼠的离体心脏和心室肌细胞将用于探索心脏功能、钙稳态和缺血/再灌注（IR）损伤恢复的性别差异。两个相互关联的假设将被测试：1。雄性和雌性离体心脏的心脏收缩功能的基本方面不同。这些收缩性调节的差异可以解释，至少在一定程度上，由细胞钙稳态的性别特异性差异。2.男性和女性心脏对缺血/再灌注损伤的反应不同。从缺血恢复的差异可以通过早期再灌注期间不同水平的钙超载来解释。钙稳态的性别特异性差异也是对IR损伤的不同反应的基础。本研究的具体目的是：1.假设检验1：A。将在从雄性和雌性小鼠分离的心脏中进行等轴测力测量。将在雄性和雌性心脏中测定钙剂量-反应曲线。B。从雄性和雌性心脏分离的单个肌细胞将加载Ca敏感性荧光染料indo- 1，并在不同刺激速率和浴[Ca]下测量颤搐收缩和细胞内钙瞬变。这些实验将确定男性和女性心脏之间的肌细胞收缩性和/或钙处理是否不同。2.假设检验2：A。在暴露于全脑缺血前和全脑缺血后再灌注后，将在离体心脏中进行等长力测量。B。在模拟IR损伤前后，将比较从雄性和雌性心脏分离的indo-1负载的肌细胞中的Ca瞬变和抽搐收缩。这些研究将为心脏功能和功能障碍的性别差异提供新的见解。

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.