Genetic disruption of poly (ADP-ribose) synthetase inhibits the expression of P-selectin and intercellular adhesion molecule-1 in myocardial ischemia/reperfusion injury

Basilia Zingarelli, Andrew L. Salzman, Csaba Szabo

Research output: Contribution to journalArticle

296 Citations (Scopus)

Abstract

The nuclear enzyme poly (ADP-ribose) synthetase (PARS) has been shown to play an important role in the pathogenesis of ischemia/reperfusion injury and circulatory shock. The aim of this study was to investigate whether PARS activity may modulate endothelial-neutrophil interaction. We present evidence that genetic disruption of PARS provides protection against myocardial ischemia and reperfusion injury by inhibiting the expression of P-selectin and intercellular adhesion molecule-1 (ICAM-1) and, consequently, by inhibiting the recruitment of neutrophils into the jeopardized tissue. Furthermore, using in vitro studies, we demonstrate that in fibroblasts lacking a functional gene for PARS, cytokine-stimulated expression of ICAM-1 is significantly reduced compared with fibroblasts from animals with a normal genotype. Similarly, in cultured human endothelial cells, oxidative- or cytokine-dependent expression of P-selectin and ICAM-1 is reduced by pharmacological inhibition of PARS by 3-aminobenzamide. These findings provide the first direct evidence that PARS activation participates in neutrophil-mediated myocardial damage by regulating the expression of P- selectin and ICAM-1 in ischemic and reperfused myocardium, and they also provide the basis for a novel therapeutic approach for the treatment of reperfusion injury.

Original languageEnglish (US)
Pages (from-to)85-94
Number of pages10
JournalCirculation Research
Volume83
Issue number1
StatePublished - Jul 13 1998
Externally publishedYes

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Poly Adenosine Diphosphate Ribose
Myocardial Reperfusion Injury
P-Selectin
Intercellular Adhesion Molecule-1
Ligases
Reperfusion Injury
Myocardial Ischemia
Neutrophils
Fibroblasts
Cytokines
Neutrophil Infiltration
Shock
Myocardium
Endothelial Cells
Genotype
Pharmacology
Enzymes
Genes

Keywords

  • 3- aminobenzamide
  • Cell adhesion molecule
  • Neutrophil
  • Nitric oxide
  • Peroxynitrite

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Genetic disruption of poly (ADP-ribose) synthetase inhibits the expression of P-selectin and intercellular adhesion molecule-1 in myocardial ischemia/reperfusion injury. / Zingarelli, Basilia; Salzman, Andrew L.; Szabo, Csaba.

In: Circulation Research, Vol. 83, No. 1, 13.07.1998, p. 85-94.

Research output: Contribution to journalArticle

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