Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA 71103, USA.
Center for Cardiovascular Diseases and Sciences and Center for Redox Biology and Cardiovascular Disease, LSU Health Sciences Center, Shreveport, LA 71103, USA.
Int J Mol Sci. 2023 Jul 1;24(13):10994. doi: 10.3390/ijms241310994.
Mental stress is a risk factor for myocardial infarction in women. The central hypothesis of this study is that restraint stress induces sex-specific changes in gene expression in the heart, which leads to an intensified response to ischemia/reperfusion injury due to the development of a pro-oxidative environment in female hearts. We challenged male and female C57BL/6 mice in a restraint stress model to mimic the effects of mental stress. Exposure to restraint stress led to sex differences in the expression of genes involved in cardiac hypertrophy, inflammation, and iron-dependent cell death (ferroptosis). Among those genes, we identified tumor protein p53 and cyclin-dependent kinase inhibitor 1A (p21), which have established controversial roles in ferroptosis. The exacerbated response to I/R injury in restraint-stressed females correlated with downregulation of p53 and nuclear factor erythroid 2-related factor 2 (Nrf2, a master regulator of the antioxidant response system-ARE). S-female hearts also showed increased superoxide levels, lipid peroxidation, and prostaglandin-endoperoxide synthase 2 (Ptgs2) expression (a hallmark of ferroptosis) compared with those of their male counterparts. Our study is the first to test the sex-specific impact of restraint stress on the heart in the setting of I/R and its outcome.
心理压力是女性心肌梗死的一个风险因素。本研究的中心假设是，束缚应激会导致心脏中基因表达出现性别特异性变化，从而由于女性心脏中氧化环境的发展，导致对缺血/再灌注损伤的反应加剧。我们在束缚应激模型中对雄性和雌性 C57BL/6 小鼠进行了挑战，以模拟心理应激的影响。暴露于束缚应激导致参与心脏肥大、炎症和铁依赖性细胞死亡（铁死亡）的基因在性别上存在差异。在这些基因中，我们确定了肿瘤蛋白 p53 和细胞周期蛋白依赖性激酶抑制剂 1A（p21），它们在铁死亡中具有争议的作用。束缚应激雌性对 I/R 损伤的反应加剧与 p53 和核因子红细胞 2 相关因子 2（Nrf2，抗氧化反应系统-ARE 的主要调节剂）的下调相关。与雄性相比，S-雌性心脏还显示出更高的超氧化物水平、脂质过氧化和前列腺素内过氧化物合酶 2（Ptgs2）表达（铁死亡的标志）。我们的研究首次在 I/R 及其结果的背景下测试了束缚应激对心脏的性别特异性影响。
