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.
Keywords: 17β-estradiol; CRHR2; Cardiomyocytes; Corticotropin-releasing hormone receptor type 2; E2; ER; EREs; Estrogens; H/R; Hypoxia/reoxygenation; IHD; IPC; LDH; Lactate Dehydrogenase; MTT; RIA; Radioimmunoassay; Sp1; Specific protein1; UCN; Urocortins; corticotrophin-releasing hormone receptor type 2; estrogen receptor; estrogen responses elements; hypoxia/reoxygenation; ischemic heart disease; ischemic preconditioning; methyl thiazolyl tetrazolium; siRNA; small interfering RNA; specific protein 1; urocortin.
Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.