Glucocorticoid Inhibition of Estrogen Regulation of the Serotonin Receptor 2B in Cardiomyocytes Exacerbates Cell Death in Hypoxia/Reoxygenation Injury.
Glucocorticoid Inhibition of Estrogen Regulation of the Serotonin Receptor 2B in Cardiomyocytes Exacerbates Cell Death in Hypoxia/Reoxygenation Injury.
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DOI：
10.1161/jaha.120.015868
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发表时间：
2021-09-07
影响因子：
5.4
通讯作者：
Cruz-Topete D
中科院分区：
文献类型：
--
作者：
Dhaibar HA;Carroll NG;Amatya S;Kamberov L;Khanna P;Orr AW;Bailey SR;Oakley RH;Cidlowski JA;Cruz-Topete D
压力已成为女性患心脏病的一个重要风险因素。研究表明，压力水平与心肌梗死后恢复延迟及死亡率上升相关。因此，我们试图探究，在心肌梗死中观察到的压力对不同性别产生的特定影响，是否部分可归因于女性性激素雌激素（E2）与主要应激激素糖皮质激素之间的基因组相互作用。
全基因组研究显示，糖皮质激素会抑制雌激素对在心肌细胞内稳态中起既定作用的基因的调控。其中包括5 - HT2BR（心脏5 - 羟色胺受体2B），其表达对于预防成体心脏中心肌细胞死亡至关重要。通过使用小干扰RNA（siRNA）、基因表达及染色质免疫沉淀测定法，我们发现5 - HT2BR是糖皮质激素受体和雌激素受体α在转录水平上的主要作用靶点。糖皮质激素受体阻止雌激素受体α募集到5 - HT2BR基因的启动子上，这可能导致绝经前女性心脏因压力而产生不良影响。通过免疫印迹法、TUNEL（脱氧核糖核苷酸末端转移酶介导的生物素 - 脱氧尿苷三磷酸缺口末端标记法）及流式细胞术，我们证明雌激素通过依赖5 - HT2BR表达的机制减少心肌细胞死亡。体外和体内实验表明，糖皮质激素会抑制雌激素对缺氧/复氧损伤的心脏保护作用，并加剧心肌梗死中的梗死面积。
这些结果揭示了在缺血/再灌注情况下，压力对女性心脏健康产生有害影响的一种新机制。
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. 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. These results established a novel mechanism underlying the deleterious effects of stress on female cardiac health in the setting of ischemia/reperfusion.
胰岛素通过鞘氨醇激酶/1-磷酸鞘氨醇轴保护凋亡心肌细胞免受缺氧/复氧损伤
影响因子：
3.7
作者：
Yu H;Che X;Xu X;Zheng M;Zhao Y;He W;Yu J;Xiong J;Li W
通讯作者：
Li W