Henno Priscilla, Maurey Christelle, Le Pimpec-Barthes Françoise, Devillier Philippe, Delclaux Christophe, Israël-Biet Dominique
Sorbonne Universités, UPMC Université Paris 06, Paris, France.
Département Physiologie-Algologie-Somnologie, Unité Fonctionnelle de Somnologie et Fonction Respiratoire, AP-HP, Hôpital Saint Antoine, 75012, Paris, France.
Respir Res. 2015 Mar 28;16(1):46. doi: 10.1186/s12931-015-0196-4.
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.
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.
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.
Overexpression and elevated activity of arginase I are involved in tobacco-induced pulmonary endothelial dysfunction.
烟草诱导的肺血管疾病部分由内皮功能障碍驱动。强效血管舒张剂一氧化氮（NO）的生物利用度取决于一氧化氮合酶3（NOS3）和精氨酸酶对其共同底物（L-精氨酸）的竞争。我们检验了吸烟通过上调精氨酸酶途径损害肺内皮功能的假说。
比较了29名吸烟者和10名从不吸烟者的肺血管环对乙酰胆碱（Ach）的离体内皮依赖性血管舒张。结果以去氧肾上腺素收缩的百分比表示。我们测试了补充L-精氨酸、精氨酸酶抑制（通过N（ω）-羟基-n-精氨酸，NorNOHA）和NOS3诱导（通过染料木黄酮）对血管舒张的影响。通过蛋白质印迹法定量肺动脉中NOS3以及精氨酸酶I和II的蛋白水平。
总体而言，吸烟者的血管舒张受损（相对于对照组；p<0.01）。29名吸烟者中的11名（ED（+）亚组）表现出内皮功能障碍（定义为对Ach无舒张反应），而18名（ED（-）亚组）血管舒张正常。ED（+）和ED（-）亚组对10（-4）M Ach的平均反应分别为-23±10%和31±4%（p<0.01）。补充L-精氨酸改善了ED（+）亚组的内皮功能（分别在存在和不存在L-精氨酸时为-4±10%和-32±10%；p = 0.006），精氨酸酶抑制也有同样效果（分别为18±9%和-1±9%；p = 0.0002）。精氨酸酶I蛋白在ED（+）样本中过表达，而ED（+）和ED（-）样本在NOS3表达方面无显著差异。染料木黄酮处理未显著改善ED（+）样本的内皮功能。
精氨酸酶I的过表达和活性升高与烟草诱导的肺内皮功能障碍有关。
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