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CLINICAL STUDIES

Polymeric-based perivascular delivery of a nitric oxide donor inhibits intimal thickening after balloon denudation arterial injury: role of nuclear factor-kappaB¹

Sanjay Kaul, MD^* , Bojan Cercek, MD, FACC^* , Jan Rengstrom, MD^*, Xiao-Ping Xu, MD^* , Mia D. Molloy, BS^* , Paul Dimayuga, BS^* , Akik K. Parikh, MD^* , Michael C. Fishbein, MD , Jan Nilsson, MD^*, Tripathi B. Rajavashisth, PhD^* and Prediman K. Shah, MD, FACC^*

^* Vascular Physiology and Thrombosis Laboratory of the Atherosclerosis Research Center, Cedars-Sinai Medical Center, Los Angeles, California, USA
Burns and Allen Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
Division of Cardiology, Cedars-Sinai Medical Center, Los Angeles, California, USA
^* Karolinska Institute, Stockholm, Sweden

Manuscript received May 29, 1998; revised manuscript received August 16, 1999, accepted October 18, 1999.

Reprint requests and correspondence: Dr. Sanjay Kaul, Division of Cardiology, Room #5314, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048
Kaul{at}cshs.org

OBJECTIVES

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.

Abbreviations and Acronyms   cGMP = cyclic guanosine monophosphate   EEL = external elastic lamina   EMSA = electrophoretic mobility shift assay   IEL = internal elastic lamina   NF-kappaB = nuclear factor-kappaB   NO = nitric oxide   PCNA = proliferating cell nuclear antigen   SPER = spermine   SPER/NO = spermine/nitric oxide   VSMC = vascular smooth muscle cell

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