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

压力会阻碍雌激素对女性心脏的抗氧化保护，从而加剧心肌缺血性损伤

• 批准号: 10715407
• 负责人: Diana Cruz Topete
• 金额: $ 21.9万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10715407
• 关键词: Adult; Affect; Aging; Behavior; Biological; Biological Assay; Biology; CDKN1A gene; COVID-19 pandemic; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cell Survival; Centers of Research Excellence; Chronic; Clinical; Collaborations; Confocal Microscopy; Data; Disease; Equilibrium; Estrogen Receptors; Estrogens; Exposure to; Female; Funding; Genomics; Glucocorticoid Receptor; Glucocorticoids; Goals; Grant; Harvest; Heart; Heart Diseases; Heart Injuries; Heart failure; Hormones; Human; Hypoxia; Imaging Techniques; Immunoprecipitation; In Vitro; Individual; Infarction; Injury; Intervention; Ischemia; Knowledge; Major Depressive Disorder; Mediating; Mental Depression; Mental disorders; Mentors; Mesenchymal Stem Cells; Modeling; Molecular; Mus; Myocardial Infarction; Myocardial Ischemia; Neonatal; Outcome; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Persons; Phenotype; Physiological; Placenta; Positioning Attribute; Predictive Value; Predisposition; Process; Production; Proteins; Psyche structure; Psychological Stress; Reactive Oxygen Species; Receptor Inhibition; Regulation; Reperfusion Injury; Reperfusion Therapy; Reporting; Research; Risk; Serum; Signal Pathway; Signal Transduction; Stress; Stress Tests; TP53 gene; Testing; Transcription Coactivator; Transcriptional Regulation; Transgenic Mice; Uncertainty; United States; Wild Type Mouse; Woman; antioxidant therapy; biological adaptation to stress; body system; cardiovascular effects; clinical predictors; experience; experimental study; global health; heart function; high risk; improved; ischemic injury; male; men; mortality risk; mouse model; nuclear factor-erythroid 2; pandemic impact; psychologic; receptor; response; restraint stress; sex; stem cells; stress disorder; stress reduction; young woman

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.

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 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 女性更容易受到压力的有害影响，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。女性已经 受这次大流行的心理影响的影响尤为严重。因此，调查这一问题至关重要 压力反应、抑郁和心血管疾病的分子途径。现在的 该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保护 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 确定压力下调细胞周期蛋白依赖性激酶抑制剂激活的机制 心肌细胞中的 1A（Cdkn1A 或 p21）和核因子红细胞 2 相关因子 2 (Nrf2) 信号转导 整个心。 p21-Nrf2 信号通路对于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（精神压力模型，导致模仿人类抑郁症的表型）抑制 雌激素受体 (ER) 介导的 p21-Nrf2 信号通路激活 缺氧/复氧。使用心脏中缺乏 GR 的转基因小鼠模型，我们将研究是否 激活该应激受体以响应心脏还原/氧化平衡的变化 通过改变雌激素信号传导导致女性心脏缺血/再灌注（I/R）损伤。我们还将测试是否恢复 p21 女性心脏中的表达（AAV 递送方法）通过减少压力后改善心脏结果 活性氧的产生。如果获得资助，该项目将提供有关心脏的重要知识 压力和抑郁在生理和分子水平上对女性心脏的影响。另外， 从这笔赠款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疗法时要考虑。