Gender-based Differences in Cardiac Calcium Regulation

心脏钙调节的性别差异

• 批准号: 6357726
• 负责人: BETH A BAILEY
• 金额: $ 12.2万
• 依托单位: URSINUS COLLEGE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-17 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6357726
• 关键词: calcium flux; calcium indicator; cardiac myocytes; cytoprotection; disease /disorder proneness /risk; gender difference; heart contraction; laboratory mouse; muscle strength; myocardial ischemia /hypoxia; neuromuscular transmission; reperfusion; tissue /cell culture

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.

男性和绝经前女性的心脏病患病率差异很大，关于女性心脏病保护机制的研究一直没有定论。从雄性和雌性小鼠分离的心脏和心室肌细胞将被用来探索基于性别的心功能、钙稳态和从缺血/再灌注(IR)损伤中恢复的差异。两个相互关联的假设将被检验：1。男性和女性离体心的心脏收缩功能的基本方面不同。这些收缩调节的差异可以解释，至少部分是由于性别不同的细胞钙稳态的差异。2.男性和女性心脏对缺血再灌注损伤的反应不同。缺血恢复的差异可以用再灌流早期不同程度的钙超载来解释。不同性别在钙稳态上的差异也是IR损伤反应差异的基础。本研究的具体目的是：1.假设1的检验：A等长力测量将在分离的雄性和雌性小鼠的心脏上进行。钙的剂量-反应曲线将在男性和女性心脏中进行测定。B.从男性和女性心脏分离的单个心肌细胞将被负载钙敏感的荧光染料Indo-1，并将在不同的刺激率和[Ca]浴下测量抽动收缩和细胞内钙瞬变。这些实验将确定男性和女性心脏的心肌细胞收缩能力和/或钙处理能力是否不同。2.假设2的检验：A.在暴露于全心缺血之前和全脑缺血后再灌流后，将在离体心中进行等长力测量。B.在模拟IR损伤前后，我们将比较含Indo-1的男性和女性心脏分离的心肌细胞的钙瞬变和抽动收缩。这些研究将为基于性别的心脏功能和功能障碍的差异提供新的见解。