17ß-Estradiol and/or Estrogen Receptor ß Attenuate the Autophagic and Apoptotic Effects Induced by Prolonged Hypoxia Through HIF-1α-Mediated BNIP3 and IGFBP-3 Signaling Blockage.

ABSTRACT

BACKGROUND/AIMS: The risk of heart disease is higher in males than in females. However, this advantage of females declines with increasing age, presumably a consequence of decreased estrogen secretion and malfunctioning of the estrogen receptor. We previously demonstrated that 17ß-estradiol (E2) prevents cardiomyocyte hypertrophy, autophagy and apoptosis via estrogen receptor α (ERα), but the effects of ERß on myocardial injury remained elusive. The present paper thus, investigated the cardioprotective effects of estrogen (E2) and ERß against hypoxia-induced cell death. METHODS: Transient transfection of Tet-On ERß gene construct was used to overexpress ERß in hypoxia-treated H9c2 cardiomyoblast cells. RESULTS: Our data revealed that IGF1R, Akt phosphorylation and Bcl-2 expression are enhanced by ERß in H9c2 cells. Moreover, ERß overexpression reduced accumulation of hypoxia-related proteins, autophagy-related proteins and mitochondria-apoptotic proteins and enhanced the protein levels of Bcl-2, pAkt and Bad under hypoxic condition. In neonatal rat ventricular myocytes (NRVMs), we observed that hypoxia induced cell apoptosis as measured by TUNEL staining, and E2 and/or ERß could totally abolish hypoxia-induced apoptosis. The suppressive effects of E2 and/or ERß in hypoxia-treated NRVMs were totally reversed by ER antagonist, ICI. Taken together, E2 and/or ERß exert the protective effect through repressed hypoxia-inducible HIF-1α, BNIP3 and IGFBP-3 levels to restrain the hypoxia-induced autophagy and apoptosis effects in H9c2 cardiomyoblast cells. CONCLUSION: The results suggest that females probably could tolerate better prolonged hypoxia condition than males, and E2/ERß treatment could be a potential therapy to prevent hypoxia-induced heart damage."