Nuclear factor-κB-mediated cell survival involves transcriptional silencing of the mitochondrial death gene BNIP3 in ventricular myocytes

Abstract

Background - A survival role for the transcription factor nuclear factor-κB (NF-κB) in ventricular myocytes has been reported; however, the underlying mechanism is undefined. In this report we provide new mechanistic evidence that survival signals conferred by NF-κB impinge on the hypoxia-inducible death factor BNIP3. Methods and Results - Activation of the NF-κB signaling pathway by IKKβ in ventricular myocytes suppressed mitochondrial permeability transition pore (PTP) opening and cell death provoked by BNIP3. Expression of IKKβ or p65 NF-κ suppressed basal and hypoxia-inducible BNIP3 gene activity. Deletion analysis of the BNIP3 promoter revealed the NF-κB elements to be crucial for inhibiting basal and inducible BNIP3 gene activity. Cells derived from p65-/-- deficient mice or ventricular myocytes rendered defective for NF-κB signaling with a nonphosphorylative IκB exhibited increased basal BNIP3 gene expression, mitochondrial PTP, and cell death. Genetic or functional ablation of the BNIP3 gene in NF-κB-defective myocytes rescued them from mitochondrial defects and cell death. Conclusions - The data provide new compelling evidence that NF-κB suppresses mitochondrial defects and cell death of ventricular myocytes through a mechanism that transcriptionally silences the death gene BNIP3. Collectively, our data provide new mechanistic insight into the mode by which NF-κB suppresses cell death and identify BNIP3 as a key transcriptional target for NF-κB-regulated expression in ventricular myocytes. © 2005 American Heart Association, Inc.