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Article Dans Une Revue Respiratory Research Année : 2015

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

Résumé

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 compared ex 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.
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Dates et versions

hal-01143464 , version 1 (17-04-2015)

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Priscilla Henno, Christelle Maurey, Françoise Le Pimpec-Barthes, Philippe Devillier, Christophe Delclaux, et al.. Is arginase a potential drug target in tobacco-induced pulmonary endothelial dysfunction?. Respiratory Research, 2015, 16 (1), pp.46. ⟨10.1186/s12931-015-0196-4⟩. ⟨hal-01143464⟩
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