Is arginase a potential drug target in tobacco-induced pulmonary endothelial dysfunction?. Issue 1 (December 2015)

• Record Type: Journal Article
• Authors: Henno, Priscilla; Maurey, Christelle; Le Pimpec-Barthes, Françoise; Devillier, Philippe; Delclaux, Christophe; Israël-Biet, Dominique
• Is Part Of: Respiratory research. Volume 16:Issue 1(2015)
• Page Start: 1
• Page End: 8
• Publication Date: 2015-12
• Subjects: Endothelial dysfunction -- Arginase -- Tobacco smoking; Respiratory organs -- Diseases -- Periodicals; 616.2005
• DOI: 10.1186/s12931-015-0196-4
• Languages: English
• ISSNs: 1465-993X

Abstract

Abstract Background Tobacco-induced pulmonary vascular disease is partly driven by endothelial dysfunction. The bioavailability of the potent vasodilator nitric oxide (NO) depends on competition between NO synthase-3 (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 comparedex vivo for pulmonary vascular rings from 29 smokers and 10 never-smokers. The results were expressed as a percentage of the contraction with phenylephrine. We tested the effects of L-arginine supplementation, arginase inhibition (by N(omega)-hydroxy-nor-l-arginine, NorNOHA) and NOS3 induction (by genistein) on vasodilation. Protein levels of NOS3 and 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. The mean responses to 10−4 M Ach were −23 ± 10% and 31 ± 4% 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. Treatment with genistein did not significantly improve endothelial function in ED+ samples. Conclusion Overexpression and elevated activity of arginase I are involved in tobacco-induced pulmonary endothelial dysfunction.