Beneficial effect of a short-acting NO donor for the prevention of neointimal hyperplasia

Abstract

Nitric oxide (NO)-based therapies effectively inhibit neointimal hyperplasia in animal models of arterial injury and bypass grafting, but are not available clinically. We created a simple, effective, locally-applied NO-eluting therapy to prevent restenosis following vascular procedures. We investigated the efficacy of perivascular delivery of two different distinctly different diazeniumdiolate NO donors, 1-[2-(carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate (PROLI/ NO), (short half-life) and diazeniumdiolated poly(acrylonitrile) (PAN/NO), (long half-life), in powder or gel form (30% poloxamer 407), at inhibiting neointimal hyperplasia using the rat carotid artery injury model. Two weeks post-injury, all of the NO-eluting therapies successfully reduced neointimal hyperplasia. However, most dramatically, PROLI/NO powder reduced intimal area by 91.2% (P<0.05) versus injury alone. PROLI/NO powder was noted to reduce the medial area (40.2% vs. injury alone, P<0.05), while other groups showed no such effect. Three days post-injury, each NO treatment group significantly reduced cellular proliferation. However, inflammatory markers revealed a distinct pattern: PAN/NO groups displayed increased leukocyte infiltration (P<0.05) whereas PROLI/NO groups displayed less macrophage infiltration (P<0.05). In conclusion, perivascular delivery of diazeniumdiolate NO donors in powder or gel form effectively inhibits neointimal hyperplasia. Application of short-acting PROLI/NO powder most effectively inhibited neointimal hyperplasia and inflammation and may represent a simple, clinically applicable NOeluting therapy to prevent neointimal hyperplasia and restenosis following open vascular interventions.

Insulin enhances the effect of nitric oxide at inhibiting neointimal hyperplasia in a rat model of type 1 diabetes

“…The neck was shaved and prepped with betadine and alcohol (75%). Following a midline neck incision, the rat carotid artery balloon injury model was performed using a 2F Fogarty catheter (generously provided by Edwards Lifesciences), as previously described (2,24,36,39). After injury and restoration of blood flow, 10 mg of the diazeniumdiolate NO donor disodium 1-[(2-carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate (PROLI/NO) was applied evenly to the external surface of the injured common carotid artery of rats in the treatment group, and the neck incision was closed.…”

“…Carotid arteries were harvested at 14 days for morphometric analysis, at which time blood was collected to measure insulin, glucose, cholesterol, and triglyceride levels. PROLI/NO was used as the diazeniumdiolate for the in vivo experiments, as it is the diazeniumdiolate NO donor that we have consistently demonstrated to be superior at inhibiting neointimal hyperplasia, compared with other diazeniumdiolates, and it is the NO donor used in our laboratory's prior study on type 2 diabetes (2,24,36).…”

Regulation of reactive oxygen species by p53: implications for nitric oxide-mediated apoptosis

“…Numerous experimental treatment options for these diseases aim at restoring NO bioavailability in the vasculature. For example, a large focus of our laboratory is the use of local NO therapy to prevent the neointimal hyperplasia and restenosis that follows many vascular interventions (1,19,36). One mechanism by which NO is able to inhibit the development of neointimal hyperplasia is via promoting VSMC apoptosis.…”

Selective phosphodiesterase-5 inhibition reduces neointimal hyperplasia in rat carotid arteries after surgical endarterectomy

“…7 In addition, evidence is growing that reduced nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling plays an important role in the pathogenesis of neointima formation, 8 which could be prevented by local delivery of NO 9 or by using a short-acting NO donor in the perivascular area of the injured rat carotid artery. 10 Furthermore, neointimal proliferation could also be attenuated by endothelial NO synthase gene transfer in a rat model of balloon injury. 11 Although there are several works that studied the effects of NO-cGMP signaling in the reduction of neointima formation through the administration of NO donors, to the best of our knowledge, there is little research on the effects of cGMP through its altered breakdown.…”