Abstract 15032: Oxygen Induces a p53-Dependent NOS3-Mediated Survival Pathway in the Infarct Myocardium by Regulating p53(Lys120) Acetylation and p53 DNA Interaction
We have recently showed that supplemental oxygen (Ox), administered as 100% O2, 60 min/day for 2 wk, was capable of promoting NOS3-dependent myocyte survival in the infarct (MI) heart. Interestingly, the proapoptotic p53, which is known to transcriptionally regulate members of the NOS family, was consistently overexpressed in the MI+Ox hearts (Fig A) with higher survival potential when compared to MI hearts. We hypothesized that p53 plays an oxygen-dependent dual role in generating apoptotic signals in the MI hearts and NOS3-mediated survival signals in the MI+Ox hearts. A 23-bp p53 response element (p53RE) was identified in NOS3 promoter and p53 was found to directly bind and transcriptionally regulate NOS3 promoter in the MI+Ox hearts. p53 from the MI heart did not bind to NOS3-p53RE and showed affinity towards apoptotic BAX-p53RE. p53 from MI+Ox heart showed affinity towards NOS3-p53RE. Analysis of p53 post-translational modifications showed differential acetylation of p53 core-domain at p53(Lys120) residue in MI and MI+Ox hearts. p53 was acetylated at Lys120 in the MI heart and oxygenation revoked this modification (Fig B). This de-acetylation functioned as the molecular switch in determining the affinity of p53 towards BAX-p53RE or NOS3-p53RE and generation of p53 pro-apoptotic and pro-survival forms. In summary, oxygenation de-acetylates p53 at the Lys120 residue and alters p53 DNA-binding affinity towards NOS3-p53RE from BAX- p53RE thus generates pro-survival form of p53 in the heart. Cardioprotection and cardiac-tissue regeneration might be achieved by generating p53-prosurvival form through inhibition of p53 core-domain post-translational modifications.
- © 2012 by American Heart Association, Inc.