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

ObjectiveIn 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.MethodsCarotid 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 PARP inhibitor, INO-1001 (5 mg/kg daily) postoperatively (n =10). After 21 days, neointima formation and vascular remodeling were assessed.ResultsImmunohistochemistry 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 mm2 ± 0.019 mm2 vs 0.089 mm2 ± 0.033 mm2 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.ConclusionsPharmacologic inhibition of PARP with INO-1001 may be a new concept to prevent neointimal hyperplasia after endarterectomy.

Clinical RelevanceNeointimal hyperplasia is a proliferative response to an arterial injury and a significant cause of bypass graft and angioplasty failure. Although there is growing evidence that reactive oxygen species and oxidative damage play an important role in restenosis, the molecular physiologic mechanism underlying the oxidative stress hypothesis is not fully understood. In the present study, we demonstrated that consistent with nitrosative stress, poly(adenosine diphosphate-ribose) polymerase (PARP) activation and apoptosis-inducing factor translocation were significantly increased in the neointima after endarterectomy. Neointima formation and inflammatory response after endarterectomy were attenuated by treatment with the PARP inhibitor INO-1001. PARP inhibition, therefore, may be a therapeutic strategy for prevention of restenosis after surgical vessel reconstruction.