Nuclear Factor-κB–Mediated Cell Survival Involves Transcriptional Silencing of the Mitochondrial Death Gene BNIP3 in Ventricular Myocytes

Author:

Baetz Delphine1,Regula Kelly M.1,Ens Karen1,Shaw James1,Kothari Shilpa1,Yurkova Natalia1,Kirshenbaum Lorrie A.1

Affiliation:

1. From the Departments of Physiology (D.B., K.M.R., K.E., N.Y., L.A.K.) and Pharmacology and Therapeutics (J.S., L.A.K.), Institute of Cardiovascular Sciences, St Boniface General Hospital Research Centre; and Manitoba Cancer Treatment Centre, Faculty of Medicine, University of Manitoba (S.K.), Winnipeg, Manitoba, Canada.

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-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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine

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