1 Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University , Xi'an, Shaanxi, China .
2 Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University , Xi'an, Shaanxi, China .
DNA Cell Biol. 2018 Oct;37(10):821-830. doi: 10.1089/dna.2018.4208. Epub 2018 Sep 18.
Premenopausal women have a reduced risk for cardiovascular disease. Estrogen deficiency augments cardiac inflammation and oxidative stress and, thereby, aggravates myocardial fibrosis (MF) and diastolic dysfunction in hypertensive female rats. However, estrogen replacement therapy has no effect on myocardial infarction and cardiac fibrosis in postmenopausal women. Further clinical studies showed that high blood glucose levels in patients with diabetes is an important cause of MF, but the underlying mechanism is unclear. To experimentally address this issue, diabetes mellitus (DM) was induced by injecting streptozotocin and administering a high-fat diet in ovariectomized (OVX) rats. High degrees of fibrosis and apoptosis were detected in the cardiac tissue of these rats, together with increased expression of iNOS. Further treatment with the G protein-coupled estrogen receptor 30 (GPR30) agonist G1 decreased iNOS expression and the apoptosis rate in cardiac tissue significantly and inhibited cardiac fibroblast (CF) proliferation. Similar trends were observed in cultured CFs treated with high concentrations of fat and glucose. In addition, treatment with the iNOS-specific inhibitor W1400 attenuated iNOS and vimentin expression, which is associated with a marked reduction in MF. These results suggest that GPR30 activation inhibits MF in diabetic OVX female rats by suppressing cardiac iNOS activity and consequently NO levels. Thus, GPR30 activation may provide novel cardioprotection strategies for postmenopausal women, especially those with DM.
绝经前女性患心血管疾病的风险较低。雌激素缺乏会加重心脏炎症和氧化应激，从而加重高血压雌性大鼠的心肌纤维化（MF）和舒张功能障碍。然而，雌激素替代疗法对绝经后女性的心肌梗死和心脏纤维化没有影响。进一步的临床研究表明，糖尿病患者的高血糖水平是 MF 的一个重要原因，但具体机制尚不清楚。为了解决这个问题，我们通过注射链脲佐菌素和给予高脂饮食在去卵巢（OVX）大鼠中诱导糖尿病。这些大鼠的心脏组织中检测到高度纤维化和细胞凋亡，同时 iNOS 的表达增加。进一步用 G 蛋白偶联雌激素受体 30（GPR30）激动剂 G1 处理，可显著降低心脏组织中 iNOS 的表达和细胞凋亡率，并抑制心脏成纤维细胞（CF）的增殖。在高浓度脂肪和葡萄糖处理的培养 CFs 中也观察到类似的趋势。此外，用 iNOS 特异性抑制剂 W1400 处理可减弱 iNOS 和波形蛋白的表达，这与 MF 的显著减少有关。这些结果表明，GPR30 激活通过抑制心脏 iNOS 活性和随后的 NO 水平抑制糖尿病 OVX 雌性大鼠的 MF。因此，GPR30 激活可能为绝经后女性，特别是患有糖尿病的女性提供新的心脏保护策略。
