title: Hypoxia suppresses myocardial survival pathway through HIF-1α-IGFBP-3-dependent signaling and enhances cardiomyocyte autophagic and apoptotic effects mainly via FoxO3a-induced BNIP3 expression.
abstract: The HIF-1α transcriptional factor and the BH-3 only protein BNIP3 are known to play fundamental roles in response to hypoxia. The objective of this research is to investigate the molecular mechanisms and the correlation of HIF-1α, BNIP3 and IGFBP-3 in hypoxia-induced cardiomyocytes injuries. Heart-derived H9c2 cells and neonatal rat ventricular myocytes (NRVMs) were incubated in normoxic or hypoxic conditions. Hypoxia increased HIF-1α expression and activated the downstream BNIP3 and IGFBP-3 thereby triggered mitochondria-dependent apoptosis. Moreover, IGF1R/PI3K/Akt signaling was attenuated by HIF-1α-dependent IGFBP-3 expression to enhance hypoxia-induced apoptosis. Autophagy suppression with 3-methyladenine or siATG5 or siBeclin-1 signiﬁcantly decreased myocardial apoptosis under hypoxia. Knockdown of FoxO3a or BNIP3 signiﬁcantly abrogated hypoxia-induced autophagy and mitochondria-dependent apoptosis. Moreover, prolonged-hypoxia induced HIF-1α stimulated BNIP3 and enhanced IGFBP-3 activation to inhibit IGF1R/PI3K/Akt survival pathway and mediate mitochondria-dependent cardiomyocyte apoptosis. HIF-1α and FoxO3a blockage are sufficient to annul the change of excessive hypoxia of hearts.
authors.affiliation: a Graduate Institute of Clinical Medical Science, Graduate Institute of Basic Medical Science, China Medical University , Taichung , Taiwan .
authors.forename: Chih-Chung
authors.initials: CC
authors.lastname: Feng
authors.affiliation: b Orthopaedic Department, Armed Forces General Hospital , Taichung , Taiwan .
authors.forename: Chien-Chung
authors.initials: CC
authors.lastname: Lin
authors.affiliation: c Graduate Institute of Basic Medical Science, China Medical University , Taichung , Taiwan .
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Lai
authors.affiliation: c Graduate Institute of Basic Medical Science, China Medical University , Taichung , Taiwan .|d Biomaterials Translational Research Center, China Medical University Hospital , Taichung , Taiwan .
authors.forename: Tung-Sheng
authors.initials: TS
authors.lastname: Chen
authors.affiliation: c Graduate Institute of Basic Medical Science, China Medical University , Taichung , Taiwan .
authors.forename: Shibu
authors.initials: S
authors.lastname: Marthandam Asokan
authors.affiliation: e Department of Nursing , Central Taiwan University of Science and Technology , Taichung , Taiwan .
authors.forename: Jing-Ying
authors.initials: JY
authors.lastname: Lin
authors.affiliation: f Emergency Department, China Medical University Hospital , Taichung , Taiwan .
authors.forename: Kuan-Ho
authors.initials: KH
authors.lastname: Lin
authors.affiliation: g Department of Biotechnology , Bharathiar University , Coimbatore , India .
authors.forename: Vijaya Padma
authors.initials: VP
authors.lastname: Viswanadha
authors.affiliation: h Department of Biological Science and Technology , China Medical University , Taichung , Taiwan .
authors.forename: Wei-Wen
authors.initials: WW
authors.lastname: Kuo
authors.affiliation: c Graduate Institute of Basic Medical Science, China Medical University , Taichung , Taiwan .|i Graduate Institute of Chinese Medical Science, China Medical University , Taichung , Taiwan , and.|j Department of Health and Nutrition Biotechnology , Asia University , Taichung , Taiwan.
authors.forename: Chih-Yang
authors.initials: CY
authors.lastname: Huang
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D015687:Cell Hypoxia; D002460:Cell Line; D002478:Cells, Cultured; D005260:Female; D000071316:Forkhead Box Protein O3 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
chemical_list: C090121:BNIP3 protein, human; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins
keywords: BNIP3; Hypoxia; IGFBP-3; apoptosis; autophagy