期刊
JOURNAL OF THE AMERICAN HEART ASSOCIATION
卷 10, 期 17, 页码 -出版社
WILEY
DOI: 10.1161/JAHA.120.015868
关键词
cardiomyocytes; estrogen; gene regulation; glucocorticoids; serotonin receptor 2b
资金
- Louisiana State University Health Sciences Center-Shreveport
- National Heart, Lung, and Blood Institute (NHBLI) [5K01HL144882-0]
- Center for Redox Biology and Cardiovascular Disease Grant [3P20GM121307-03S1]
- National Institutes of Health [HL098435, HL133497, HL141155]
- Intramural Research Program of the National Institutes of Health
Stress has been identified as a significant risk factor for heart disease in women, possibly due to genomic interactions between estrogen and glucocorticoids that inhibit gene expression critical for cardiomyocyte homeostasis. These interactions may contribute to worsened outcomes after myocardial infarction in premenopausal women.
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 alpha at the level of transcription. The glucocorticoid receptor blocks the recruitment of estrogen receptor alpha 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.
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