PT  - JOURNAL ARTICLE
AU  - Priscilla Henno
AU  - Christelle Maurey
AU  - Françoise Le Pimpec-Barthes
AU  - Philippe Devillier
AU  - Christophe Delclaux
AU  - Dominique Israël-Biet
TI  - Is arginase a potential drug target in tobacco-induced pulmonary endothelial dysfunction?
AID  - 10.1183/13993003.congress-2015.PA4904
DP  - 2015 Sep 01
TA  - European Respiratory Journal
PG  - PA4904
VI  - 46
IP  - suppl 59
4099  - http://erj.ersjournals.com/content/46/suppl_59/PA4904.short
4100  - http://erj.ersjournals.com/content/46/suppl_59/PA4904.full
SO  - Eur Respir J2015 Sep 01; 46
AB  - 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.