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Abstract：
Estrogens have been suggested to exert cardioprotection through maintaining endogenous cardioprotective mechanisms. In the present study, we investigated whether estrogens protect cardiomyocytes against hypoxia/reoxygenation (H/R) via modulating urocortins (UCNs) and their receptor corticotrophin-releasing hormone receptor type 2 (CRHR2). We found that 17β-estradiol (E2) enhanced UCN cardioprotection against H/R and increased CRHR2 expression in neonatal rat cardiomyocytes. E2 protected cardiomyocytes against H/R, which was impaired by CRHR2 antagonist or knockdown of CRHR2. Estrogen receptor α (ERα) antagonist treatment or ERα knockdown could abolish E2-induced CRHR2 up-regulation. Moreover, knockdown of Sp1 also attenuated E2-induced CRHR2 up-regulation. Ovariectomy resulted in down-regulation of CRHR2 and Sp-1 in myocardium of mice, which was restored by E2 or ERα agonist treatment. These results suggest that estrogens act on ERα to up-regulate CRHR2 expression in cardiomyocytes, thereby enhancing cardioprotection of UCNs against H/R.
摘要：
已经提出雌激素通过维持内源性心脏保护机制来发挥心脏保护作用。在本研究中,我们研究了雌激素是否通过调节尿皮质素(UCNs)及其受体促肾上腺皮质激素释放激素受体2型(CRHR2)来保护心肌细胞免受缺氧/复氧(H/R).我们发现17β-雌二醇（E2）增强了UCN对H/R的心脏保护作用，并增加了新生大鼠心肌细胞中的CRHR2表达。E2保护心肌细胞抵抗H/R，受到CRHR2拮抗剂或CRHR2敲低的损害。雌激素受体α（ERα）拮抗剂治疗或ERα敲低可以消除E2诱导的CRHR2上调。此外，Sp1的敲低也减弱了E2诱导的CRHR2上调。卵巢切除导致小鼠心肌CRHR2和Sp-1下调,通过E2或ERα激动剂治疗恢复。这些结果表明雌激素作用于ERα以上调心肌细胞中CRHR2的表达,从而增强UCN对H/R的心脏保护作用。
