Bcl-2 intersects the NfκB signalling pathway and suppresses apoptosis in ventricular myocytes

As a first step toward identifying putative regulators of apoptosis in the heart, the impact of the anti-apoptosis protein Bcl-2 (B-cell lymphoma gene) on the NF kappaB (nuclear factor kappa beta) signalling pathway in suppressing apoptosis in ventricular myocytes was studied. The data indicate that adenovirus-mediated delivery of Bcl-2 resulted in a significant increase in NF kappaB-dependent DNA binding and NF kappaB-directed gene transcription. No change in NF kappaB protein content was observed in myocytes expressing Bcl-2. Moreover, the Bcl-2-mediated NF kappaB activation was found to be related to changes in the activity of the NF kappaB regulatory protein I kappaB alpha (inhibitor of kappa beta). In this regard, a marked reduction in I kappaB alpha protein content was observed in ventricular myocytes expressing Bcl-2. The mode by which Bcl-2 regulates I kappaB alpha was related to the N-terminal phosphorylation and degradation of I kappaB alpha by the proteasome since an N-terminal deletion mutant of I kappaB alpha or the proteasome inhibitor lactacystin abrogated Bcl-2's inhibitory effects on I kappaB alpha and prevented NF kappaB activation. Furthermore, adenovirus-mediated delivery of a phosphorylation defective form of I kappaB alpha rendered ventricular myocytes incapable of NF kappaB activation and susceptible to tumour necrosis factor alpha-mediated apoptosis. Moreover, Bcl-2's anti-apoptotic function was lost in cells defective for NF kappaB activation. The data provide evidence for a link between Bcl-2 and the NF kappaB signalling pathway for the suppression of apoptosis in ventricular myocytes.