Stress Exacerbates Myocardial Ischemic Injury by Blocking Estrogen's Antidoxidant Protection in the Female Heart

项目摘要 与新冠肺炎疫情相关的心理压力导致了前所未有的增加 应激障碍。高压力水平与临床抑郁症和心血管疾病密切相关。在……里面 与男性相比，女性对精神压力对心血管的影响更敏感。尤其是年轻的 女性对压力的有害影响有更高的敏感性，而且压力水平也有所增加 与女性心脏病发作后较高的死亡率和并发症风险相关。女人们一直是 不成比例地受到这场大流行的心理影响。因此，关键是要调查 应激反应、抑郁和心血管疾病的分子途径。现在 一项旨在测试主要应激激素糖皮质激素的增加是否抑制雌激素保护的提案 通过改变心肌细胞的还原/氧化状态来影响女性心脏。为了实现这一目标，我们建议 确定应激下调细胞周期蛋白依赖性激酶抑制物激活的机制 1A(CDKN1A或p21)和核因子红系相关因子2(Nrf2)在心肌细胞中的信号转导和 整颗心。P21-Nrf2信号通路是限制氧化应激损伤的关键 体外缺氧/再灌注损伤。我们将研究糖皮质激素受体(GR)的激活是否通过 抑制压力(导致人类抑郁症表型的精神压力模型)抑制 雌激素受体(ER)介导的p21-Nrf2信号通路的激活 缺氧/复氧。使用心脏中缺乏GR的转基因小鼠模型，我们将调查 应激受体的激活对心脏还原/氧化平衡变化的反应 雌激素信号转导机制对女性心脏缺血再灌注损伤的影响我们还将测试是否恢复p21 在女性心脏中的表达(AAV递送途径)通过减少应激后的心脏结局来改善心脏结局 产生活性氧物种。如果得到资助，这个项目将提供有关心脏疾病的关键知识 压力和抑郁在生理和分子水平上对女性心脏的影响。另外， 从这项资助中描述的实验中收集的数据将促进性作为一个因素的重要性 在考虑心脏病和衰竭的抗氧化剂治疗时，请考虑一下。

PROJECT ABSTRACT The psychological stress associated with the COVID-19 pandemic has led to an unprecedented increase in stress disorders. High-stress levels closely correlate with clinical depression and cardiovascular disease. In contrast to men, women are more reactive to the cardiovascular effects of mental stress. In particular, young women have a higher susceptibility to the harmful effects of stress, and increased stress levels have been shown to correlate with a higher risk of mortality and complications after a heart attack in women. Women have been disproportionally affected by the psychological effects of this pandemic. Therefore, it is critical to investigate the molecular pathways underlying the stress response, depression, and cardiovascular disease. The present proposal aims to test if increases in the primary stress hormones glucocorticoids inhibit estrogen protection in the female heart by altering the reductive/oxidative state in cardiomyocytes. To accomplish this goal, we propose identifying the mechanism whereby stress downregulates the activation of the cyclin-dependent kinase inhibitor 1A (Cdkn1A or p21) and the nuclear factor erythroid-2-related factor 2 (Nrf2) signaling in cardiomyocytes and the whole heart. The p21-Nrf2 signaling pathway is essential to limit oxidative stress damage in hypoxia/reperfusion injury in vitro. We will investigate if the activation of the glucocorticoid receptor (GR) by restraining stress (model of mental stress which leads to a phenotype that mimics depression in humans) inhibits the estrogen receptor (ER)-mediated activation of the p21-Nrf2 signaling pathway in the context of hypoxia/reoxygenation. Using a transgenic mouse model lacking the GR in the heart, we will investigate if the activation of this stress receptor to changes in cardiac reductive/oxidative balance in response to ischemia/reperfusion (I/R) injury in female hearts by altering estrogen signaling. We will also test if restoring p21 expression (AAV delivery approach) in female hearts improves the cardiac outcomes after stress by reducing the production of reactive oxygen species. If funded, this project will provide critical knowledge on the cardiac consequences of stress and depression at the physiological and molecular level for the female heart. Also, the data gathered from the experiments described in this grant will promote the importance of sex as a factor to consider when considering antioxidant therapies in heart disease and failure.