Abstract P3105: Stress Exacerbates Ischemia/reperfusion Injury In The Female Heart Through The Glucocorticoid Receptor Signaling In Cardiomyocytes

It is estimated that over 30,000 women younger than 55-years-old die of acute myocardial infarction (AMI) in the United States annually. Clinical data suggest that exposure to mental stress exacerbates the outcomes of an AMI in women. However, a knowledge gap exists regarding the molecular mechanisms whereby stress contributes to AMI in women and how they differ in men. The present project aims to define the mechanisms underlying the link between stress, glucocorticoids (stress hormones), the glucocorticoid receptor (GR) signaling, and the worse outcomes of AMI in females than in their male counterparts. We challenged male and female transgenic mice lacking GR in cardiomyocytes (cardioGRKO) and their respective wild-type controls in a murine model of "mental" stress followed by ischemia/reperfusion (AMI) injury. Our data show that stress exacerbated the response to AMI injury in control females compared to their male counterparts. Females without cardiomyocyte GR were protected and presented significantly reduced infarct areas compared to cardioGRKO males and control males and females with intact GR signaling. These results demonstrated that stress directly affected the heart and that these effects are sexually dimorphic. The severity of the infarct and cardiomyocyte death was further exacerbated during the highest estrogen activity phase (proestrus) of the female cycle. Our in vitro studies additionally supported these data, showing that glucocorticoids block estrogen's pro-survival effects on cardiomyocytes in hypoxia/re-oxygenation conditions in a mechanism dependent upon GR inhibition of estrogen regulation of antioxidant pathways, including decreased levels of the master regulator of the antioxidant response, nuclear factor-erythroid factor 2-related factor 2 (Nrf2), and increased superoxide and lipid peroxides production. Our in vivo models displayed similar findings. Our study is the first to test the impact of mental stress on activating glucocorticoid signaling in the heart in the setting of AMI. This study is relevant to human health as a proof of concept that exposure to high stress levels aggravates AMI in premenopausal hearts by cardiomyocyte GR-regulated mechanisms that may be targeted to develop therapies tailored to women.