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

D Baetz, KM Regula, K Ens, J Shaw, S Kothari… - Circulation, 2005 - Am Heart Assoc
D Baetz, KM Regula, K Ens, J Shaw, S Kothari, N Yurkova, LA Kirshenbaum
Circulation, 2005Am Heart Assoc
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 …
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-κB 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.
Am Heart Assoc