期刊
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
卷 50, 期 3, 页码 471-478出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2010.11.006
关键词
Myocardial infarction; p53; Pifithrin-alpha; Apoptosis; MMP-2
资金
- Deutsche Forschungsgemeinschaft [EB 419/1-2]
- Martin Luther University
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 H2O2-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. (C) 2010 Elsevier Ltd. All rights reserved.
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