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(Circulation Research. 2006;99:1347.)
© 2006 American Heart Association, Inc.

Molecular Medicine

Transcriptional Silencing of the Death Gene BNIP3 by Cooperative Action of NF-B and Histone Deacetylase 1 in Ventricular Myocytes

James Shaw, Tong Zhang, Marek Rzeszutek, Natalia Yurkova, Delphine Baetz, James R. Davie, Lorrie A. Kirshenbaum

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

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

Earlier we identified a survival role for NF-B in ventricular myocytes, however, the underlying mechanism was undefined. In this report we provide new mechanistic evidence that the hypoxia-inducible death factor BNIP3 is transcriptionally silenced by NF-B through a mechanism that involves the cooperative actions of HDAC1. Activation of the NF-B signaling pathway in ventricular myocytes suppressed basal and hypoxia-inducible BNIP3 gene activity. Basal Bnip3 gene expression was increased in cells derived from p65^–/– deficient mice. The histone deacetylase (HDAC) inhibitor Trichostatin A (TSA 10 nM) suppressed the inhibitory actions of NF-B on Bnip3 gene transcription. Basal and hypoxia- induced Bnip3 transcription was repressed by wild type but not a catalytically inactive mutant of HDAC1. Immunoprecipitation assays verified interaction of HDAC1 with wild type p65 NF-B and mutations of p65 defective for transactivation in ventricular myocytes. Deletion analysis revealed canonical NF-B elements within the Bnip3 promoter to be important for repression of Bnip3 gene expression by HDAC1. Further, the ability of HDAC1 to repress Bnip3 gene transcription was lost in cells derived from p65^–/– deficient mice but was restored by repletion of p65 NF-B into p65^–/– cells. Mutations of p65 NF-B defective for DNA binding but not for transactivation abrogated the inhibitory actions of HDAC1 on the Bnip3 gene transcription. Together, our findings provide new mechanistic insight into the cytoprotective actions conferred by NF-B that extend to the active transcriptional repression of the death factor Bnip3 through a mechanism that is mutually dependent on HDAC-1.

Key Words: ventricular myocytes • apoptosis • NF-B • cell culture

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