Polymeric-based perivascular delivery of a nitric oxide donor inhibits intimal thickening after balloon denudation arterial injury: Role of nuclear factor-kappaB

OBJECTIVES To examine the effect of a polymeric-based periadventitial deliv ery of a nitric oxide (NO)-releasing diazeniumdiolate, spermine/NO (SPER/NO ), on balloon injury-induced neointimal hyperplasia in rat ileofemoral arte ries. BACKGROUND Reduced local bioavailability and adverse side effects limit sys temic administration of NO to modulate vascular response to injury. METHODS A polylactic-polyglycolic acid polymeric-matrix containing 2.5% SPE R/NO (w/w) was applied around the injured arteries. Quantitative histomorph ometry was performed at day 14, proliferating cell nuclear antigen (PCNA) i mmunohistochemistry at day 3 to assess effects on smooth muscle proliferati on and electrophoretic mobility shift assay to evaluate effects on transcri ption factor, nuclear factor-kappaB (NF-kappaB). RESULTS Treatment with SPER/NO reduced the intimal area (0.011 +/- 0.009 vs . 0.035 +/- 0.006 mm(2) control, p < 0.01) and the intima to media ratio (0 .089 +/- 0.062 vs. 0.330 +/- 0.057 control, p < 0.005). Spermine/nitric oxi de produced a profound inhibition of PCNA-positive cells (>75%, p < 0.005) and significantly suppressed the injury-induced activation of NF-kappaB. Va scular cyclic guanosine monophosphate (cCMP) levels were elevated after tre atment with the SPER/NO (0.28 +/- 0.03 vs. 0.17 +/- 0.02-pmol/mg tissue con trol, p < 0.01). The inhibitory effects on neointimal proliferation were:lo calized to the site of application of SPER/NO and were not associated with any changes in platelet aggregation or bleeding time. Neither SPER nor poly mer alone had any significant effects on any of the variables examined. CONCLUSIONS Polymeric-based perivascular delivery of a NO donor produces a marked localized inhibition of neointimal proliferation in balloon-injured arteries. This phenomenon is associated with suppression of NF-kappaB activ ation and elevation of the vascular cGMP at the site of injury. (J Am Cell Cardiol 2000;35:493-501) (C) 2000 by the American College of Cardiology.