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

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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.