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

The HIF-1 alpha 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-1 alpha, 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-1 alpha expression and activated the downstream BNIP3 and IGFBP-3 thereby triggered mitochondria dependent apoptosis. Moreover, IGF1R/PI3K/Akt signaling was attenuated by HIF-1 alpha-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 Fox03a or BNIP3 significantly abrogated hypoxia-induced autophagy and mitochondria-dependent apoptosis. Moreover, prolonged-hypoxia induced H1F-1 alpha stimulated BNIP3 and enhanced IGFBP-3 activation to inhibit IGF1R/P13K/Akt survival pathway and mediate mitochondria-dependent cardiomyocyte apoptosis. H1F-1 alpha and Fox03a blockage are sufficient to annul the change of excessive hypoxia of hearts.