Sex differences in myocardial ischemia/reperfusion injury

描述（由申请人提供）：在所有心血管相关疾病中，冠状动脉疾病仍然是西方国家死亡的主要原因。男性和女性心脏病的发病率和进展明显不同，表明性别偏见因素可以预防疾病。该项目的长期目标是确定受性染色体和性腺激素调节的影响心血管疾病的过程，提高对疾病内源性机制的理解，并确定可能成为治疗目标的性别偏见保护因素。本项目采用新颖的小鼠模型，该模型已经为XX和XY小鼠对心肌缺血/再灌注损伤的反应存在显著差异提供了新的证据，而这种差异与小鼠的性腺性别无关。这些新模型在具有相同性腺类型的小鼠中改变性染色体的数量或类型，从而首次了解XX与XY染色体的差异效应。与XY小鼠相比，XX小鼠对缺血/再灌注损伤的易感性显著增加，缺血后心脏收缩功能降低。XX和XY的差异是由于X染色体的数量，而不是Y染色体的存在与否。因此，X染色体含有以剂量依赖和性别偏倚的方式强烈影响缺血/再灌注损伤的因子。目的1是利用这些小鼠模型，通过测量心功能恢复和梗死面积、线粒体功能、超氧化物产生和保护性信号转导途径，研究XX和XY差异的生理和分子机制。目的2是首先确定导致XX与XY差异的候选X基因列表，然后通过操纵特定候选基因在体内的表达来测试其作用。用不同剂量的特定候选X基因测量小鼠对缺血/再灌注损伤的反应。目的3：通过控制成年性腺激素水平和性腺类型，了解雌激素和雄激素如何作用于XX和XY小鼠对缺血/再灌注损伤的保护作用。对缺血性损伤的反应将作为激素水平、性染色体补体和年龄的函数来测量。区分女性和男性之间差异的激素和染色体后果将为理解保护免受缺血/再灌注损伤的因素提供必要的基础，并着眼于利用保护因素开发新的治疗方法。

DESCRIPTION (provided by applicant): Among all cardiovascular-related diseases, coronary artery disease still remains the leading cause of death in western countries. The incidence and progression of heart disease is markedly different in males and females, indicating that sex-biased factors can protect from disease. The long term objectives of this project are to identify processes, regulated by sex chromosomes and gonadal hormones, that affect cardiovascular disease, to improve the understanding of endogenous mechanisms of disease, and to identify sex-biased protective factors that may become targets for therapies. The project utilizes novel mouse models, which have already provided new evidence for striking differences in the response of XX and XY mice to myocardial ischemia/reperfusion injury, independent of the gonadal sex of the mice. These novel models vary the number or type of sex chromosomes in mice that have the same type of gonad, and thus allow the first understanding of the differential effects of XX vs. XY chromosomes. XX mice show dramatically greater susceptibility to ischemia/reperfusion injury, relative to XY mice, and lower post-ischemic heart contractile function. The XX vs. XY difference is attributable to the number of X chromosomes, not the presence/absence of the Y chromosome. Thus, the X chromosome harbors factors that strongly influence ischemia/reperfusion injury in a dose-dependent and sexually biased manner. Aim 1 is to investigate the physiological and molecular mechanisms that account for the XX vs. XY difference using these mouse models by measuring heart functional recovery and infarct size, mitochondrial function, superoxide production, and protective signal transduction pathways. Aim 2 is to first identify a list of candidate X gene(s) responsible for the XX vs. XY difference, and then to test the role of specific candidate genes by manipulating their expression in vivo. . Response to ischemia/reperfusion injury will be measured in mice with different doses of specific candidate X genes. Aim 3 is to manipulate the levels of adult gonadal hormones and type of gonad to understand how estrogens and androgens act on XX and XY mice to cause protection from ischemia/reperfusion injury. Response to ischemic insult will be measured as a function of hormonal level, sex chromosome complement and age. Discriminating the hormonal vs. chromosomal consequences of differences between females and males will provide an essential foundation for understanding factors that protect from ischemia/reperfusion injury, with an eye toward harnessing the protective factors to develop novel therapies.