Genetic disruption of poly (ADP-ribose) synthetase inhibits the expression of P-selectin and intercellular adhesion molecule-1 in myocardial ischemia/reperfusion injury.
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.
Zingarelli
B
B
Children's Hospital Medical Center, Division of Critical Care, Cincinnati, Ohio 45229, USA. bzingarelli@chmcc.org
Salzman
A L
AL
Szabó
C
C
D000818:Animals; D002465:Cell Movement / Q000502:physiology; D003327:Coronary Disease / Q000473:pathology; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D017353:Gene Deletion; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D051379:Mice; D017202:Myocardial Ischemia / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D009206:Myocardium / Q000473:pathology; D009504:Neutrophils / Q000502:physiology; D009566:Nitrates / Q000378:metabolism; D019007:P-Selectin / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics*
D009566:Nitrates; D019007:P-Selectin; D018799:Intercellular Adhesion Molecule-1; C039642:peroxynitric acid; D011065:Poly(ADP-ribose) Polymerases