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

Background-A survival role for the transcription factor nuclear factor-kappa B (NF-kappa B) 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-kappa B impinge on the hypoxia-inducible death factor BNIP3. Methods and Results-Activation of the NF-kappa B signaling pathway by IKK beta in ventricular myocytes suppressed mitochondrial permeability transition pore (PTP) opening and cell death provoked by BNIP3. Expression of IKK beta or p65 NF-kappa B suppressed basal and hypoxia- inducible BNIP3 gene activity. Deletion analysis of the BNIP3 promoter revealed the NF-kappa B 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-kappa B signaling with a nonphosphorylative I kappa B exhibited increased basal BNIP3 gene expression, mitochondrial PTP, and cell death. Genetic or functional ablation of the BNIP3 gene in NF-kappa B-defective myocytes rescued them from mitochondrial defects and cell death. Conclusions-The data provide new compelling evidence that NF-kappa B 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-kappa B suppresses cell death and identify BNIP3 as a key transcriptional target for NF-kappa B-regulated expression in ventricular myocytes.