Abstract 363: Transcriptional Silencing of the Death Gene BNIP3 by Cooperative Action of Nuclear Factor-Kappa Beta and Histone Deacetylase 1 in Ventricular Myocytes
In this report we provide new mechanistic evidence that the hypoxia-inducible death factor Bnip3 is transcriptionally silenced by NF-κB through a mechanism that involves the cooperative actions of HDAC1. Activation of the NF-κB 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 or ventricular myocytes rendered defective for NF-κB signaling. The histone deacetylase (HDAC) inhibitor Trichostatin A (TSA 10–100nM) abrogated the inhibitory actions of NF-κB 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 p65 NF-κB with HDAC1 in ventricular myocytes. Deletion analysis revealed canonical NF-κB elements within the Bnip3 promoter to be crucial 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-κB into p65−/− cells. Mutations of p65 NF-κB defective for DNA binding but not for transactivation abrogated the inhibitory actions of HDAC1 on the Bnip3 gene transcription. Together, our novel findings provide new mechanistic insight into the cytoprotective actions conferred by NF-κB that extend to the active transcriptional repression of the death factor Bnip3 through a mechanism that is mutually dependent upon HDAC-1.