title: Impaired iNOS-sGC-cGMP signalling contributes to chronic hypoxic and hypercapnic pulmonary hypertension in rat.
abstract: Nitric oxide (NO) is an important vascular modulator in the development of pulmonary hypertension. NO exerts its regulatory effect mainly by activating soluble guanylate cyclase (sGC) to synthesize cyclic guanosine monophosphate (cGMP). Exposure to hypoxia causes pulmonary hypertension. But in lung disease, hypoxia is commonly accompanied by hypercapnia. The aim of this study was to examine the changes of sGC enzyme activity and cGMP content in lung tissue, as well as the expression of inducible nitric oxide synthase (iNOS) and sGC in rat pulmonary artery after exposure to hypoxia and hypercapnia, and assess the role of iNOS-sGC-cGMP signal pathway in the development of hypoxic and hypercapnic pulmonary hypertension. Male Sprague-Dawley rats were exposed to hypoxia and hypercapnia for 4 weeks to establish model of chronic pulmonary hypertension. Weight-matched rats exposed to normoxia served as control. After exposure to hypoxia and hypercapnia, mean pulmonary artery pressure, the ratio of right ventricle/left ventricle+septum, and the ratio of right ventricle/body weight were significantly increased. iNOS mRNA and protein levels were significantly increased, but sGC α(1) mRNA and protein levels were significantly decreased in small pulmonary arteries of hypoxic and hypercapnic exposed rat. In addition, basal and stimulated sGC enzyme activity and cGMP content in lung tissue were significantly lower after exposure to hypoxia and hypercapnia. These results demonstrate that hypoxia and hypercapnia lead to the upregulation of iNOS expression, downregulation of sGC expression and activity, which then contribute to the development of pulmonary hypertension.
authors.affiliation: Department of Respiratory Medicine, The Second Affiliated Hospital, Wenzhou Medical College, Wenzhou, Zhejiang, China.
authors.forename: Xiao-dong
authors.initials: XD
authors.lastname: Xia
authors.forename: Zheng-jie
authors.initials: ZJ
authors.lastname: Xu
authors.forename: Xiao-guang
authors.initials: XG
authors.lastname: Hu
authors.forename: Cheng-yun
authors.initials: CY
authors.lastname: Wu
authors.forename: Yuan-rong
authors.initials: YR
authors.lastname: Dai
authors.forename: Lei
authors.initials: L
authors.lastname: Yang
mesh_terms: D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism*; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism*; D006352:Heart Ventricles / Q000503:physiopathology; D006935:Hypercapnia / Q000150:complications*; D006976:Hypertension, Pulmonary / Q000201:enzymology / Q000209:etiology / Q000378:metabolism*; D000860:Hypoxia; D008168:Lung / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D011651:Pulmonary Artery / Q000201:enzymology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000071756:Soluble Guanylyl Cyclase; D015854:Up-Regulation; D016276:Ventricular Function
chemical_list: D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP