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Sodium Nitrite Protects Against Vascular Injury And Reduces Smooth Muscle Cell Proliferation And Endothelial Cell Activation

Raghuveer Vallabhaneni, Sara Crissman, Brian S Zuckerbraun, Edith Tzeng ∙
University of Pittsburgh, Pittsburgh, PA

Background: Nitric oxide (NO) can protect against intimal hyperplasia following arterial injury. Strategies to deliver NO to prevent intimal hyperplasia in experimental models have included gene therapy, drug eluting stents, or inhaled NO. All of these strategies have potential negative side effects. The anion nitrite, most often thought of as a stable metabolite of NO, has been shown to be converted to NO in the setting of hypoxia or tissue injury thus acting as a circulating NO donor. We hypothesized that inhaled nebulized sodium nitrite reduces intimal hyperplasia following carotid injury. Methods: Sprague-Dawley rats were administered nebulized sodium nitrite (1.5 mg/min) for twenty minutes. Balloon injury to the left internal carotid artery was performed. Arteries were harvested 20 days after injury and underwent hematoxylin and eosin (H&E) staining. Intimal and medial areas of injured arteries were measured and intima:media (I:M) ratios were calculated. Primary rat aortic smooth muscle cells (SMC) or rat aortic endothelial cells (EC) were used for in vitro experiments (passages 3-8). Proliferation assays were performed by measuring 3H-thymidine incorporation. Western blotting was used to determine changes in protein levels. Results: Inhaled nebulized sodium nitrite reduced intimal hyperplasia by 77±7% compared to untreated injured carotids as determined by I:M ratios (P<0.01). Sodium nitrite (5-25 μM) significantly decreased SMC proliferation at 24 hours (P < 0.05). Additionally, nitrite reduced tumor necrosis factor-alpha (TNF-a)-induced increases in endothelin-1, e-selectin protein, and HO-1. Conclusions: Inhaled nebulized sodium nitrite inhibits intimal hyperplasia in vivo and SMC proliferation/endothelial cell activation in vitro. This may prove to be a useful therapeutic adjunct in the treatment of vascular disease and in the prevention of intimal hyperplasia formation.