Glucocorticoid Inhibition of Estrogen Regulation of the Serotonin Receptor 2B in Cardiomyocytes Exacerbates Cell Death in Hypoxia/Reoxygenation Injury

Abstract

Background Stress has emerged as an important risk factor for heart disease in women. Stress levels have been shown to correlate with delayed recovery and increased mortality after a myocardial infarction. Therefore, we sought to investigate if the observed sex‐specific effects of stress in myocardial infarction may be partly attributed to genomic interactions between the female sex hormones, estrogen (E2), and the primary stress hormones glucocorticoids. Methods and Results Genomewide studies show that glucocorticoids inhibit estrogen‐mediated regulation of genes with established roles in cardiomyocyte homeostasis. These include 5‐HT2BR (cardiac serotonin receptor 2B), the expression of which is critical to prevent cardiomyocyte death in the adult heart. Using siRNA, gene expression, and chromatin immunoprecipitation assays, we found that 5‐HT2BR is a primary target of the glucocorticoid receptor and the estrogen receptor α at the level of transcription. The glucocorticoid receptor blocks the recruitment of estrogen receptor α to the promoter of the 5‐HT2BR gene, which may contribute to the adverse effects of stress in the heart of premenopausal women. Using immunoblotting, TUNEL (terminal deoxynucleotidal transferase–mediated biotin–deoxyuridine triphosphate nick‐end labeling), and flow cytometry, we demonstrate that estrogen decreases cardiomyocyte death by a mechanism relying on 5‐HT2BR expression. In vitro and in vivo experiments show that glucocorticoids inhibit estrogen cardioprotection in response to hypoxia/reoxygenation injury and exacerbate the size of the infarct areas in myocardial infarction. Conclusions These results established a novel mechanism underlying the deleterious effects of stress on female cardiac health in the setting of ischemia/reperfusion.

Military sexual trauma and incident hypertension: a 16-year cohort study of young and middle-aged men and women

“…Another investigation of middle-aged women from the general population indicated that sexual assault was associated with a three to four-fold greater odds of a high carotid plaque score and the progression of carotid atherosclerosis over 5 years, although there were no associations with carotid intima-media thickness [44]. Most recently, a study suggested that traumatic stress might change the genomic interactions between glucocorticoid receptors and estrogen receptors, and thereby inhibit the cardioprotection that women typically experience from the hormone estrogen [45]. Although a paucity of data concerns the physiological effects of MST or other types of sexual violence in men, we can begin to theorize about these pathways based on literature concerning trauma, PTSD and cardiovascular risk.…”

Serotonin Receptors in Myocardial Infarction: Friend or Foe?

“…This cardiomyocyte protection is abolished by glucocorticoids, the main stress hormones, and therefore important in the context of women exposed to stress suffering from a heart attack. 129 Under physiological conditions, regulation of blood pressure occurs via 5-HT2AR signaling, whose activation induces vasoconstriction. 56 However, in a deoxycorticosterone acetate (DOCA)-salt-hypertensive rat model, which resembles human volume-overload induced chronic hypertension, contractions insensitive to the 5-HT2AR antagonist ketanserin were detected, together with increased 5-HT2BR expression.…”

“…Receptor activation or overexpression was further shown to lead to adverse remodeling with more collagen formation and reduced cardiac functions, while treatment with antagonists terguride and SB204741 reduced collagen deposition and fibrosis. − , Interestingly, the important female sex hormone estrogen can prevent cardiomyocyte death by binding to an estrogen responsive element, which regulates 5-HT2BR transcription. This cardiomyocyte protection is abolished by glucocorticoids, the main stress hormones, and therefore important in the context of women exposed to stress suffering from a heart attack …”

Women’s mood at high altitude. sexual dimorphism in hypoxic stress modulation by the tryptophan–melatonin axis

“…By modulating the expression of the 5-HT receptor— 5-HT2BR— estrogens decrease cardiomyocyte death that occurs in response to hypoxia/re-oxygenation injury. Glucocorticoids, on the other hand, prevent 5-HT–mediated estrogen cardioprotection, exacerbating the size of the infarct areas in myocardial infarction ( Dhaibar et al, 2021 ). 5-HT protection by estrogens, being cancelled by glucocorticoids, evidence the deleterious effects that stress may have on women’s well-being, particularly under hypoxic conditions.…”