title: Chronic Normobaric Hypoxia Induces Pulmonary Hypertension in Rats: Role of NF-κB.
abstract: To investigate whether nuclear factor-kappa B (NF-κB) activation is involved in chronic normobaric hypoxia-induced pulmonary hypertension (PH), rats were treated with saline or an NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC, 150 mg/kg, sc, twice daily), and exposed to normoxia or chronic normobaric hypoxia with a fraction of inspired oxygen of ∼0.1 for 14 days. Lung tissue levels of NF-κB activity, and interleukin (IL)-1β, IL-6, and cyclooxygenase-2 mRNAs, were determined, and mean pulmonary arterial pressure, right ventricular hypertrophy, and right heart function were evaluated. Compared to the normoxia exposure group, rats exposed to chronic normobaric hypoxia showed an increased NF-κB activity, measured by increased nuclear translocation of p50 and p65 proteins, an increased inflammatory gene expression in the lungs, elevated mean pulmonary arterial blood pressure and mean right ventricular pressure, right ventricular hypertrophy, as assessed by right ventricle-to-left ventricle plus septum weight ratio, and right heart dysfunction. Treatment of hypoxia-exposed rats with PDTC inhibited NF-κB activity, decreased pulmonary arterial blood pressure and right ventricular pressure, and ameliorated right ventricular hypertrophy and right heart dysfunction. Hypoxia exposure increased protein kinase C activity and promoted pulmonary artery smooth muscle cell proliferation in vitro. Our data suggest that NF-κB activation may contribute to chronic normobaric hypoxia-induced PH.
authors.affiliation: 1 Institute of Hypoxia Medicine, Wenzhou Medical University , Wenzhou, Zhejiang, China .
authors.forename: Junming
authors.initials: J
authors.lastname: Fan
authors.affiliation: 1 Institute of Hypoxia Medicine, Wenzhou Medical University , Wenzhou, Zhejiang, China .
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Fan
authors.affiliation: 1 Institute of Hypoxia Medicine, Wenzhou Medical University , Wenzhou, Zhejiang, China .
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: 1 Institute of Hypoxia Medicine, Wenzhou Medical University , Wenzhou, Zhejiang, China .
authors.forename: Lu
authors.initials: L
authors.lastname: Ding
authors.affiliation: 1 Institute of Hypoxia Medicine, Wenzhou Medical University , Wenzhou, Zhejiang, China .
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Zheng
authors.affiliation: 1 Institute of Hypoxia Medicine, Wenzhou Medical University , Wenzhou, Zhejiang, China .
authors.forename: Jinbin
authors.initials: J
authors.lastname: Guo
authors.affiliation: 1 Institute of Hypoxia Medicine, Wenzhou Medical University , Wenzhou, Zhejiang, China .
authors.forename: Dongmei
authors.initials: D
authors.lastname: Xia
authors.affiliation: 1 Institute of Hypoxia Medicine, Wenzhou Medical University , Wenzhou, Zhejiang, China .
authors.forename: Feng
authors.initials: F
authors.lastname: Xue
authors.affiliation: 1 Institute of Hypoxia Medicine, Wenzhou Medical University , Wenzhou, Zhejiang, China .
authors.forename: Yongyu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 2 The Feinstein Institute for Medical Research and Hofstra North Shore LIJ School of Medicine , Manhasset, New York.
authors.forename: Shufang
authors.initials: S
authors.lastname: Liu
authors.affiliation: 1 Institute of Hypoxia Medicine, Wenzhou Medical University , Wenzhou, Zhejiang, China .
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Gong
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D001274:Atmospheric Pressure; D049109:Cell Proliferation; D051546:Cyclooxygenase 2 / Q000235:genetics; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000209:etiology*; D017380:Hypertrophy, Right Ventricular / Q000209:etiology / Q000503:physiopathology; D000860:Hypoxia / Q000150:complications* / Q000188:drug therapy / Q000503:physiopathology; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D011651:Pulmonary Artery / Q000503:physiopathology; D011759:Pyrrolidines / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013859:Thiocarbamates / Q000627:therapeutic use; D016278:Ventricular Function, Right / Q000502:physiology
chemical_list: D000975:Antioxidants; D053583:Interleukin-1beta; D015850:Interleukin-6; D016328:NF-kappa B; D011759:Pyrrolidines; D012333:RNA, Messenger; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid; D051546:Cyclooxygenase 2; D011493:Protein Kinase C
keywords: hypoxia; inflammation; nuclear factor-kappa B; pulmonary artery smooth muscle cells; pulmonary hypertension