Inhibition of p53 after acute myocardial infarction: reduction of apoptosis is counteracted by disturbed scar formation and cardiac rupture

J Mol Cell Cardiol. 2011 Mar;50(3):471-8. doi: 10.1016/j.yjmcc.2010.11.006. Epub 2010 Nov 11.

Abstract

Cardiomyocyte apoptosis, partially mediated through p53 signaling pathway, plays a crucial role in the progression of pathological remodeling and heart failure following myocardial infarction (MI). We hypothesized that pifithrin-alpha (PFTa), a synthetic p53 inhibitor, would suppress cardiac apoptosis through the disruption of p53-dependent transcriptional activation and thereby improve heart function in a mouse model of MI. In our experiments we show that PFTa blocked p53 transcriptional activity and attenuated H(2)O(2)-induced cardiac apoptosis in cultured neonatal rat cardiomyocytes. Additionally, administration of PFTa in mice after acute MI in vivo led to a significant reduction of cardiomyocyte apoptosis but in parallel caused an increase of infarct size and significantly reduced 7-day survival rate. Subsequent analysis revealed significantly reduced proliferation and cell number, diminished collagen deposition, and elevated MMP-2 activity at the infarct zone of PFTa-treated hearts. In homozygous p53 deficient mice (p53(-/-)), however, PFTa treatment did not interfere with scar formation and did not increase MMP-2 activity after MI. Collectively, our data suggest that although p53-inhibition through PFTa reduces cardiomyocyte apoptosis, in the setting of acute MI this assumed beneficial effect is severely counteracted by the adverse remodeling of the infarct zone. PFTa increases MMP-2 activity in a p53-dependent manner, which seems a major contributor to instability of the forming scar and consequently leads to infarct progression and ventricular rupture.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Benzothiazoles / pharmacology*
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Collagen / metabolism
  • Heart Rupture / pathology
  • Hydrogen Peroxide / pharmacology
  • Male
  • Matrix Metalloproteinase 2 / metabolism
  • Mice
  • Myocardial Infarction / drug therapy
  • Myocardial Infarction / genetics
  • Myocardial Infarction / metabolism
  • Myocardial Infarction / pathology*
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / drug effects
  • Rats
  • Toluene / analogs & derivatives*
  • Toluene / pharmacology
  • Transcriptional Activation / drug effects
  • Tumor Suppressor Protein p53 / antagonists & inhibitors*
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Benzothiazoles
  • Tumor Suppressor Protein p53
  • Toluene
  • Collagen
  • Hydrogen Peroxide
  • pifithrin
  • Matrix Metalloproteinase 2