title: 17β-Estradiol and/or Estrogen Receptor β Attenuate the Autophagic and Apoptotic Effects Induced by Prolonged Hypoxia Through HIF-1α-Mediated BNIP3 and IGFBP-3 Signaling Blockage.
abstract: OBJECTIVE
  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 17β-estradiol (E2) prevents cardiomyocyte hypertrophy, autophagy and apoptosis via estrogen receptor α (ERα), but the effects of ERβ on myocardial injury remained elusive. The present paper thus, investigated the cardioprotective effects of estrogen (E2) and ERβ against hypoxia-induced cell death.
  
  
  METHODS
  Transient transfection of Tet-On ERβ gene construct was used to overexpress ERβ in hypoxia-treated H9c2 cardiomyoblast cells.
  
  
  RESULTS
  Our data revealed that IGF1R, Akt phosphorylation and Bcl-2 expression are enhanced by ERβ in H9c2 cells. Moreover, ERβ 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 ERβ could totally abolish hypoxia-induced apoptosis. The suppressive effects of E2 and/or ERβ in hypoxia-treated NRVMs were totally reversed by ER antagonist, ICI. Taken together, E2 and/or ERβ 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.
  
  
  CONCLUSIONS
  The results suggest that females probably could tolerate better prolonged hypoxia condition than males, and E2/ERβ treatment could be a potential therapy to prevent hypoxia-induced heart damage."
authors.affiliation: School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung,Taiwan.
authors.forename: Dennis Jine-Yuan
authors.initials: DJ
authors.lastname: Hsieh
authors.forename: Wei-Wen
authors.initials: WW
authors.lastname: Kuo
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Lai
authors.forename: Marthandam Asokan
authors.initials: MA
authors.lastname: Shibu
authors.forename: Chia-Yao
authors.initials: CY
authors.lastname: Shen
authors.forename: Peiying
authors.initials: P
authors.lastname: Pai
authors.forename: Yu-Lan
authors.initials: YL
authors.lastname: Yeh
authors.forename: Jing-Ying
authors.initials: JY
authors.lastname: Lin
authors.forename: Vijaya Padma
authors.initials: VP
authors.lastname: Viswanadha
authors.forename: Chih-Yang
authors.initials: CY
authors.lastname: Huang
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D002478:Cells, Cultured; D004958:Estradiol / Q000494:pharmacology*; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D047629:Estrogen Receptor beta; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018972:Insulin-Like Growth Factor Binding Protein 3; D008565:Membrane Proteins; D004958:Estradiol