Activation of the peroxynitrite-poly(adenosine diphosphate-ribose) polymerase pathway during neointima proliferation:: A new target to prevent restenosis after endarterectomy

Objective: In a rat model of endarterectomy, we investigated the potential role of the peroxynitrite-poly(adenosine diphosphate[ADP]-ribose) polymerase (PARP) pathway in neointima formation and the effect of pharmacologic inhibition of PARP on vascular remodeling. Methods: Carotid endarterectomy was performed in male Sprague-Dawley rats by incision of the left carotid artery with removal of intima. Three groups were studied: sham-operated rats (n = 10), control rats with endarterectomy (n = 10) or rats with endarterectomy treated with the PAR-P inhibitor, INO-1001 (5 mg/kg daily) postoperatively (n =10). After 21 days, neointima formation and vascular remodeling were assessed. Results: Immunohistochemistry analysis demonstrated activation of the peroxynitrite-PARP pathway with significant staining for nitrotyrosine, poly(ADP-ribose), and nuclear translocation of apoptosis-inducing factor (AIF) in the neointima of the control group. Treatment with INO-1001 significantly reduced the neointima area (0.024 mm(2) +/- 0.019 mm(2) VS 0.089 mm(2) +/- 0.033 mm(2) in the control group), the neointima/media thickness ratio (0.81 +/- 0.05 vs 2.76 +/- 1.57 in the control group), and the inflammation score (0.1 +/- 0.07 vs; 0.3 +/- 0.12 in the control group) after endarterectomy. Conclusions. Pharmacologic inhibition of PARP with INO-1001 may be a new concept to prevent neointimal hyperplasia after endarterectomy.