Is arginase a potential drug target in tobacco-induced pulmonary endothelial dysfunction?

Abstract

Background: Tobacco-induced pulmonary vascular disease is partly driven by endothelial dysfunction. The bioavailability of NO depends on competition between NOS3 and arginases for their common substrate (L-arginine). We tested the hypothesis whereby tobacco smoking impairs pulmonary endothelial function via upregulation of the arginase pathway.

Methods: Endothelium-dependent vasodilation in response to acetylcholine (Ach) was compared ex vivo for pulmonary vascular rings from 29 smokers and 10 never-smokers. We tested the effects of L-arginine supplementation, arginase inhibition (by NorNOHA) and NOS3 induction (by genistein) on vasodilation. Protein levels of NOS3, arginases I and II in the pulmonary arteries were quantified by Western blotting.

Results: Overall, vasodilation was impaired in smokers (relative to controls; p<0.01). Eleven of the 29 smokers (the ED⁺ subgroup) displayed endothelial dysfunction (defined as the absence of a relaxant response to Ach), whereas 18 (the ED^- subgroup) had normal vasodilation (-23±10% vs 31±4% at Ach 10^-4M in the ED⁺ and ED^- subgroups, respectively, p<0.01). Supplementation with L- arginine improved endothelial function in the ED⁺ subgroup (-4±10% vs. -32±10% in the presence and absence of L- arginine, respectively; p=0.006), as did arginase inhibition (18±9% vs. -1±9%, respectively; p=0.0002). Arginase I protein was overexpressed in ED⁺ samples, whereas ED⁺ and ED^- samples did not differ significantly in terms of NOS3 expression. Genistein did not improve endothelial function in ED⁺ samples.

Conclusion: Overexpression and elevated activity of arginase I are involved in tobacco-induced pulmonary endothelial dysfunction.