Poly (ADP-ribose) synthetase modulates expression of P-selectin and intercellular adhesion molecule-1 in myocardial ischemia-reperfusion injury

B. Zingarelli, A. L. Salzman, Csaba Szabo

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Activation of the nuclear enzyme poly (ADP ribose) synthetase (PARS), subsequent to oxidant-dependent DNA damage, plays an important role in the pathogenesis of reperfusion injury. Here we investigated whether genetic ablation of PARS affects the expression of P-selectin and intercellular adhesion molecule-1 (ICAM 1) in myocardial ischemia and reperfusion. In wild type mice, 1h occlusion of the left anterior descendent coronary artery followed by 1h reperfusion resulted in a marked myocardial injury, indicated by a marked increase in serum creatinine phosphokinase levels. Absence of a functional PARS gene resulted in a significant prevention of reperfusion injury: serum creatine phosphokinase was reduced by 40%. Neutrophil infiltration in myocardial tissue, as measured by the activity of myeloperoxidase, was significantly elevated after myocardial ischemia and reperfusion in wild-type mice. The elevation of the enzyme correlated with formation of nitrotyrosine, a marker of peroxynitrite, in the reperfused tissue. Immunohistochemical evaluation for adhesion molecules indicated a significant expression of P-selectin mainly in endothelial cells and an enhancement of ICAM-1 expression in endothelial cells and myocytes. In PARS-/- mice tissue myeloperoxidase activity was significantly reduced and nitrotyrosine staining was virtually abolished after reperfusion. Genetic disruption of PARS also inhibited the expression of P-selectin and ICAM-1 in the reperfused myocardium. In fibroblasts lacking a functional gene for PARS, expression of ICAM-1 after stimulation with tumor necrosis factor or interleukin-1 was reduced in comparison to normal fibroblasts. These findings provide direct evidence that PARS regulates the expression of P-selectin and ICAM-1.

Original languageEnglish (US)
JournalFASEB Journal
Volume12
Issue number5
StatePublished - Mar 20 1998
Externally publishedYes

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ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology

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