Abstract 3860: Constitutive Basal Repression of the Mitochondrial Death Protein Bnip3 by NF-kB Averts Cell Death of Post-natal Ventricular Myocytes
Apoptosis has been posited as an underlying feature of ventricular remodeling and contractile failure post-myocardial infarction. Herein, we describe a novel survival paradigm whereby death signals elicited by E2F-1 are blocked by NF-kB. We specifically show that NF-kB plays a pivotal role in maintaining basal cell survival of cardiac myocytes by a mechanism that inhibits E2F-1 dependent activation of the mitochondrial death protein Bnip3. Under non-apoptosis conditions, ChIP analysis of post-natal ventricular myocytes revealed the p65 NF-kB subunit constitutively bound to the Bnip3 promoter, whereas E2F-1 was relatively undetectable. Conversely, E2F-1 Bnip3 promoter binding, Bnip3 gene transcription and cell death were markedly increased in cardiac myocytes during hypoxia. This coincided with a reduction in p65NF-kB activity. IKKβ- mediated activation of NF-kB disrupted E2F-1 Bnip3 promoter binding, and inhibited Bnip3 gene transcription and cell death. Moreover, in absence of hypoxia, basal Bnip3 promoter activity and gene expression were dramatically increased in p65−/− cells and ventricular myocytes rendered deficient for NF-kB signaling. Genetic knock-down of E2F-1 abrogated the increased basal Bnip3 gene transcription and cell death in ventricular myocytes deficient for NF-κB signaling. Activation of the survival kinase PI3K/Akt pathway inhibited Bnip3 expression levels in a manner dependent upon a functional IKKb-NF-kB signaling pathway. Hence, the constitutive repression of Bnip3 gene activation by NF-kB is crucial for averting cell death under basal and hypoxia- inducible conditions in post-natal ventricular myocytes.