HIF-1 alpha acts as the cellular rheostat for oxygen sensing in cardiomyocytes. Overexpression of HIF-1 alpha in the heart during acute myocardial infarction (MI) is known to attenuate cardiac dysfunction by upregulating pro-angiogenic HIF-1 alpha target genes. However, the effect of HIF-1 alpha overexpression on hypoxic cardiomyocyte apoptosis still remains obscure. In this study, we report for the first time that myocardium-targeted nanotized HIF-1 alpha overexpression during MI downregulates cardiomyocyte apoptosis. HIF-1 alpha overexpression attenuates bnip3-mediated apoptosis indirectly by promoting HO-1-induced anti-oxidant response. Chromatin immunoprecipitation experiment revealed that HIF-1 alpha overexpression in hypoxic cardiomyocytes increases binding of HIF-1 alpha to the hypoxia-responsive element in the promoter of its target anti-oxidant gene ho-1 which is known to attenuate ROS accumulation. ROS accumulation in hypoxic cardiomyocytes causes cysteine oxidation of the DNA-binding p50 subunit of NF kappa B, which hampers NF kappa B binding to KB-responsive genes like bnip3. Downregulated oxidative stress due to HIF-1 alpha overexpression leads to decline in cysteine oxidation of NF kappa Bp50, causing NF kappa B to bind to the promoter of bnip3 as a transcriptional repressor. Therefore HIF-1 alpha overexpressionmediated attenuation of cardiomyocyte apoptosis occurs by transcriptional repression of bnip3 by NF kappa B. Our study thus reveals that downregulation of bnip3-mediated cardiomyocyte apoptosis occurs via ho-1 upregulation upon HIF-1 alpha overexpression during MI, despite both being HIF-1 alpha target genes. The cross-regulation of HIF-1 alpha and NF kappa B-mediated pathways effectively downregulates apoptosis due to HIF-1 alpha overexpression during MI, which can be exploited for possible therapeutic intervention. (C) 2020 Elsevier Inc. All rights reserved.