title: Inhibition of p53 after acute myocardial infarction: reduction of apoptosis is counteracted by disturbed scar formation and cardiac rupture.
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.
authors.affiliation: Department of Medicine III, University of Halle-Wittenberg, Ernst-Grube-Strasse 40, 06097 Halle, Germany.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Katharina
authors.initials: K
authors.lastname: Köhler
authors.forename: Jia
authors.initials: J
authors.lastname: Xu
authors.forename: Di
authors.initials: D
authors.lastname: Lu
authors.forename: Thomas
authors.initials: T
authors.lastname: Braun
authors.forename: Axel
authors.initials: A
authors.lastname: Schlitt
authors.forename: Michael
authors.initials: M
authors.lastname: Buerke
authors.forename: Ursula
authors.initials: U
authors.lastname: Müller-Werdan
authors.forename: Karl
authors.initials: K
authors.lastname: Werdan
authors.forename: Henning
authors.initials: H
authors.lastname: Ebelt
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D052160:Benzothiazoles / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D006341:Heart Rupture / Q000473:pathology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D009203:Myocardial Infarction / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects; D051381:Rats; D014050:Toluene / Q000031:analogs & derivatives* / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D052160:Benzothiazoles; D016159:Tumor Suppressor Protein p53; D014050:Toluene; D003094:Collagen; D006861:Hydrogen Peroxide; C121565:pifithrin; D020778:Matrix Metalloproteinase 2