Increased Rho-kinase expression and activity and pulmonary endothelial dysfunction in smokers with normal lung function.
Endothelial dysfunction is one of the main consequences of the toxic effects of cigarette smoke on the vascular system. Increasing evidence suggests that the small G-protein RhoA and its downstream effectors, the Rho-kinases (ROCKs), are involved in systemic endothelial dysfunction induced by cigarette smoke. This study aimed to evaluate the role of the RhoA/ROCKs pathway in pulmonary artery endothelial function in current smokers with normal lung function. Lung tissues were obtained from nonsmokers and smokers who underwent lobectomy for lung carcinoma. Arterial relaxation in response to acetylcholine (ACh) was assessed in isolated pulmonary arterial rings. Protein expressions and activities of endothelial nitric oxide synthase (eNOS), ROCKs and the myosin phosphatase subunit 1 (MYPT-1) were sought. Relaxation in response to ACh was significantly lower in smokers as compared with nonsmokers (n = 8 in each group), consistent with reduced eNOS activity in the former compared with the latter. eNOS protein expression remained, however, the same in both groups. Expression of ROCKs, guanosine triphosphate-RhoA and phosphorylated MYPT-1 were significantly increased in smokers compared with controls. Pulmonary endothelial dysfunction is present in smokers whose lung function has not yet been impaired. Reduced activity of eNOS accounts at least in part for this endothelial dysfunction. Increased expression and activity of ROCKs accounts for another part through direct or indirect inhibition of the Rho-A/ROCKs pathway on nitric oxide synthesis and sustained pulmonary vasoconstriction through inhibition of myosin phosphatase.
Duong-Quy
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S
Service de Physiologie - Explorations Fonctionnelles, Hôpital Cochin, 27 rue du Faubourg, Saint-Jacques, 75104 Paris, France.
Dao
P
P
Hua-Huy
T
T
Guilluy
C
C
Pacaud
P
P
Dinh-Xuan
A T
AT
D000109:Acetylcholine / Q000494:pharmacology; D000368:Aged; D002283:Carcinoma, Bronchogenic / Q000201:enzymology / Q000601:surgery; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008175:Lung Neoplasms / Q000201:enzymology / Q000601:surgery; D008297:Male; D008875:Middle Aged; D043263:Myosin-Light-Chain Phosphatase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D012129:Respiratory Function Tests; D012907:Smoking / Q000378:metabolism* / Q000473:pathology; D014661:Vasoconstriction / Q000187:drug effects; D054460:rho-Associated Kinases / Q000096:biosynthesis*; D020742:rhoA GTP-Binding Protein / Q000096:biosynthesis
D052250:Nitric Oxide Synthase Type III; D054460:rho-Associated Kinases; D043263:Myosin-Light-Chain Phosphatase; C490372:PPP1R12A protein, human; D020742:rhoA GTP-Binding Protein; D000109:Acetylcholine