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(Circulation. 2005;112:3777-3785.)
© 2005 American Heart Association, Inc.

Molecular Cardiology

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

Delphine Baetz, PhD^*; Kelly M. Regula, PhD^*; Karen Ens, MSc; James Shaw, BSc; Shilpa Kothari, MSc; Natalia Yurkova, PhD; Lorrie A. Kirshenbaum, PhD

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.

Correspondence to Dr Lorrie A. Kirshenbaum, Institute of Cardiovascular Sciences, St Boniface General Hospital Research Centre, Room 3016, 351 Taché Ave, Winnipeg, Manitoba, Canada R2H 2A6. E-mail Lorrie{at}sbrc.ca

Received July 6, 2005; revision received September 2, 2005; accepted October 3, 2005.

Background— A survival role for the transcription factor nuclear factor-B (NF-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-B impinge on the hypoxia-inducible death factor BNIP3.

Methods and Results— Activation of the NF-B signaling pathway by IKKß in ventricular myocytes suppressed mitochondrial permeability transition pore (PTP) opening and cell death provoked by BNIP3. Expression of IKKß or p65 NF-B suppressed basal and hypoxia-inducible BNIP3 gene activity. Deletion analysis of the BNIP3 promoter revealed the NF-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-B signaling with a nonphosphorylative IB exhibited increased basal BNIP3 gene expression, mitochondrial PTP, and cell death. Genetic or functional ablation of the BNIP3 gene in NF-B–defective myocytes rescued them from mitochondrial defects and cell death.

Conclusions— The data provide new compelling evidence that NF-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-B suppresses cell death and identify BNIP3 as a key transcriptional target for NF-B–regulated expression in ventricular myocytes.

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