p53's choice of myocardial death or survival: Oxygen protects infarct myocardium by recruiting p53 on NOS3 promoter through regulation of p53-Lys(118) acetylation

EMBO Mol Med. 2013 Nov;5(11):1662-83. doi: 10.1002/emmm.201202055. Epub 2013 Oct 1.


Myocardial infarction, an irreversible cardiac tissue damage, involves progressive loss of cardiomyocytes due to p53-mediated apoptosis. Oxygenation is known to promote cardiac survival through activation of NOS3 gene. We hypothesized a dual role for p53, which, depending on oxygenation, can elicit apoptotic death signals or NOS3-mediated survival signals in the infarct heart. p53 exhibited a differential DNA-binding, namely, BAX-p53RE in the infarct heart or NOS3-p53RE in the oxygenated heart, which was regulated by oxygen-induced, post-translational modification of p53. In the infarct heart, p53 was heavily acetylated at Lys(118) residue, which was exclusively reversed in the oxygenated heart, apparently regulated by oxygen-dependent expression of TIP60. The inhibition of Lys(118) acetylation promoted the generation of NOS3-promoting prosurvival form of p53. Thus, oxygenation switches p53-DNA interaction by regulating p53 core-domain acetylation, promoting a prosurvival transcription activity of p53. Understanding this novel oxygen-p53 survival pathway will open new avenues in cardioprotection molecular therapy.

Keywords: NOS3; lysine acetylation; myocardial infarction; oxygenation; p53.

MeSH terms

  • Acetylation
  • Apoptosis*
  • Cell Survival
  • Gene Expression Regulation
  • Humans
  • Lysine / genetics
  • Lysine / metabolism*
  • Myocardial Infarction / genetics
  • Myocardial Infarction / metabolism*
  • Myocardial Infarction / physiopathology
  • Myocardium / cytology*
  • Myocardium / metabolism
  • Nitric Oxide Synthase Type III / genetics*
  • Nitric Oxide Synthase Type III / metabolism
  • Oxygen / metabolism*
  • Promoter Regions, Genetic*
  • Protein Binding
  • Tumor Suppressor Protein p53 / chemistry
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*


  • Tumor Suppressor Protein p53
  • NOS3 protein, human
  • Nitric Oxide Synthase Type III
  • Lysine
  • Oxygen