title: 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 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.
  
  
  CONCLUSIONS
  Overexpression and elevated activity of arginase I are involved in tobacco-induced pulmonary endothelial dysfunction.
authors.affiliation: Sorbonne Universités, UPMC Université Paris 06, Paris, France. priscilla.henno@sat.aphp.fr.|Département Physiologie-Algologie-Somnologie, Unité Fonctionnelle de Somnologie et Fonction Respiratoire, AP-HP, Hôpital Saint Antoine, 75012, Paris, France. priscilla.henno@sat.aphp.fr.|Laboratoire de Pharmacologie Respiratoire UPRES EA 220, Hôpital Foch, 92150, Suresnes, France. priscilla.henno@sat.aphp.fr.
authors.forename: Priscilla
authors.initials: P
authors.lastname: Henno
authors.affiliation: Ecole Nationale Vétérinaire d'Alfort, Unité de Médecine, Université Paris-Est, 94700, Maisons-Alfort, France. cmaurey@vet-alfort.fr.
authors.forename: Christelle
authors.initials: C
authors.lastname: Maurey
authors.affiliation: Sorbonne Paris Cité, Université Paris-Descartes, Paris, France. francoise.lepimpec-barthes@egp.aphp.fr.|Service de Chirurgie Thoracique, AP-HP, Hôpital Européen Georges Pompidou, 75015, Paris, France. francoise.lepimpec-barthes@egp.aphp.fr.
authors.forename: Françoise
authors.initials: F
authors.lastname: Le Pimpec-Barthes
authors.affiliation: Laboratoire de Pharmacologie Respiratoire UPRES EA 220, Hôpital Foch, 92150, Suresnes, France. P.DEVILLIER@hopital-foch.org.|Université Versailles Saint-Quentin en Yvelines, UFR Sciences de la Santé Simone Veil, Montigny le Bretonneux, France. P.DEVILLIER@hopital-foch.org.
authors.forename: Philippe
authors.initials: P
authors.lastname: Devillier
authors.affiliation: Sorbonne Paris Cité, Université Paris-Descartes, Paris, France. christophe.delclaux@egp.aphp.fr.|Service de Physiologie, Explorations Fonctionnelles Respiratoires et du Sommeil, AP-HP, Hôpital Européen Georges Pompidou, 75015, Paris, France. christophe.delclaux@egp.aphp.fr.
authors.forename: Christophe
authors.initials: C
authors.lastname: Delclaux
authors.affiliation: Sorbonne Paris Cité, Université Paris-Descartes, Paris, France. dominique.israel-biet@egp.aphp.fr.|Service de Pneumologie, AP-HP, Hôpital Européen Georges Pompidou, 75015, Paris, France. dominique.israel-biet@egp.aphp.fr.
authors.forename: Dominique
authors.initials: D
authors.lastname: Israël-Biet
mesh_terms: D000328:Adult; D000368:Aged; D001119:Arginase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001120:Arginine / Q000378:metabolism; D016022:Case-Control Studies; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D015398:Signal Transduction; D012907:Smoking / Q000009:adverse effects* / Q000378:metabolism / Q000503:physiopathology; D015854:Up-Regulation; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D014665:Vasodilator Agents; D001120:Arginine; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C574619:ARG1 protein, human; C477631:ARG2 protein, human; D001119:Arginase