GPR30 Attenuates Myocardial Fibrosis in Diabetic Ovariectomized Female Rats: Role of iNOS Signaling
GPR30 Attenuates Myocardial Fibrosis in Diabetic Ovariectomized Female Rats: Role of iNOS Signaling
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GPR30 减轻糖尿病卵巢切除雌性大鼠的心肌纤维化：iNOS 信号传导的作用
DOI：
10.1089/dna.2018.4208
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发表时间：
2018
影响因子：
3.1
通讯作者：
Shiqiang Yu
中科院分区：
文献类型：
--
作者：
Xiaowu Wang;Yanzhen Tan;Bo Xu;Linhe Lu;Minggao Zhao;Jipeng Ma;Hongliang Liang;Jincheng Liu;Shiqiang Yu
绝经前妇女患心血管疾病的风险降低。雌激素缺乏增加心脏炎症和氧化应激，从而加重高血压雌性大鼠心肌纤维化（MF）和舒张功能障碍。然而，雌激素替代疗法对绝经后妇女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的重要原因，但其潜在机制尚不清楚。为了解决这一问题，我们在切除卵巢（OVX）的大鼠中注射链脲佐菌素并给予高脂肪饮食诱导糖尿病（DM）。大鼠心脏组织高度纤维化和凋亡，iNOS表达增加。进一步应用G蛋白偶联雌激素受体30 （GPR30）激动剂G1可显著降低心肌组织iNOS表达和凋亡率，抑制心肌成纤维细胞（CF）增殖。在用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治疗可以减弱iNOS和vimentin的表达，这与MF的显著降低有关。这些结果表明GPR30激活通过抑制心脏iNOS活性和NO水平抑制糖尿病OVX雌性大鼠MF。因此，激活GPR30可能为绝经后妇女，特别是糖尿病患者提供新的心脏保护策略。
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.