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

AbstractOBJECTIVES:
To examine the effect of a polymeric-based periadventitial delivery of a nitric oxide (NO)-releasing diazeniumdiolate, spermine/NO (SPER/NO), on balloon injury-induced neointimal hyperplasia in rat ileofemoral arteries.
BACKGROUND:
Reduced local bioavailability and adverse side effects limit systemic administration of NO to modulate vascular response to injury.
METHODS:
A polylactic-polyglycolic acid polymeric matrix containing 2.5% SPER/NO (w/w) was applied around the injured arteries. Quantitative histomorphometry was performed at day 14, proliferating cell nuclear antigen (PCNA) immunohistochemistry at day 3 to assess effects on smooth muscle proliferation and electrophoretic mobility shift assay to evaluate effects on transcription factor, nuclear factor-kappaB (NF-kappaB).
RESULTS:
Treatment with SPER/NO reduced the intimal area (0.011 +/- 0.009 vs. 0.035 +/- 0.006 mm2 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 oxide produced a profound inhibition of PCNA-positive cells (>75%, p < 0.005) and significantly suppressed the injury-induced activation of NF-kappaB. Vascular cyclic guanosine monophosphate (cGMP) levels were elevated after treatment with the SPER/NO (0.28 +/- 0.03 vs. 0.17 +/- 0.02 pmol/mg tissue control, p < 0.01). The inhibitory effects on neointimal proliferation were localized to the site of application of SPER/NO and were not associated with any changes in platelet aggregation or bleeding time. Neither SPER nor polymer 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 activation and elevation of the vascular cGMP at the site of injury.
AuthorsS Kaul, B Cercek, J Rengstrom, X P Xu, M D Molloy, P Dimayuga, A K Parikh, M C Fishbein, J Nilsson, T B Rajavashisth, P K Shah
JournalJournal of the American College of Cardiology (J Am Coll Cardiol) Vol. 35 Issue 2 Pg. 493-501 (Feb 2000) ISSN: 0735-1097 [Print] United States
PMID10676700 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • NF-kappa B
  • Polymers
  • Proliferating Cell Nuclear Antigen
  • Polylactic Acid-Polyglycolic Acid Copolymer
  • Polyglycolic Acid
  • Spermine
  • Nitric Oxide
  • Lactic Acid
  • Cyclic GMP
Topics
  • Angioplasty, Balloon (adverse effects)
  • Animals
  • Arteries (drug effects, injuries, pathology)
  • Bleeding Time
  • Cell Division (drug effects)
  • Cyclic GMP (metabolism)
  • Drug Delivery Systems
  • Hyperplasia (metabolism, pathology, prevention & control)
  • Lactic Acid
  • Male
  • NF-kappa B (metabolism)
  • Nitric Oxide (metabolism)
  • Platelet Aggregation
  • Polyglycolic Acid
  • Polylactic Acid-Polyglycolic Acid Copolymer
  • Polymers
  • Proliferating Cell Nuclear Antigen (metabolism)
  • Rats
  • Rats, Sprague-Dawley
  • Spermine (administration & dosage)
  • Tunica Intima (drug effects, injuries, pathology)

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