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

项目摘要 与COVID-19大流行相关的心理压力导致了前所未有的 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 与男子相比，妇女对精神压力造成的心血管影响的反应更大。尤其是年轻 女性更容易受到压力的有害影响，并且已经显示出压力水平的增加 与女性心脏病发作后死亡率和并发症风险较高有关。妇女 受到这场流行病的心理影响。因此，调查 压力反应、抑郁症和心血管疾病的潜在分子途径。本 这项提案旨在测试主要应激激素糖皮质激素的增加是否会抑制雌激素的保护作用， 通过改变心肌细胞中的还原/氧化状态来改变女性心脏。为了实现这一目标，我们建议 鉴定应激下调细胞周期蛋白依赖性激酶抑制剂的活化的机制 1A（Cdkn 1A或p21）和核因子红细胞-2相关因子2（Nrf 2）信号传导， 整个心脏。p21-Nrf 2信号通路对限制氧化应激损伤至关重要， 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（导致类似人类抑郁症的表型的精神压力模型）抑制 雌激素受体（ER）介导的p21-Nrf 2信号通路的激活， 缺氧/复氧。使用心脏缺乏GR的转基因小鼠模型，我们将研究是否 这种应激受体的激活对心脏还原/氧化平衡的变化作出反应， 缺血/再灌注（I/R）损伤的女性心脏通过改变雌激素信号。我们还将测试是否恢复p21 在女性心脏中的AAV表达（AAV递送方法）通过减少应激后的心脏结局， 产生活性氧如果获得资助，该项目将提供关于心脏病的关键知识， 压力和抑郁在生理和分子水平上对女性心脏的影响。还 从这项资助中描述的实验中收集的数据将促进性别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要考虑。

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.