title: Glycoprotein 130 Inhibitor Ameliorates Monocrotaline-Induced Pulmonary Hypertension in Rats.
abstract: Pulmonary arterial hypertension (PAH) is characterized by vasoconstriction, vascular remodelling, and microthrombotic events. Inflammatory cytokine interleukin (IL-6) may be a key factor in the development of PAH, and glycoprotein 130 (Gp130) is an important signal-transducing subunit of IL-6. The aim of our study was to evaluate the effectiveness of Gp130 inhibitor in reducing inflammation and ameliorating PAH-related vascular remodelling in monocrotaline (MCT)-exposed rats.
  
  
  
  Sprague-Dawley rats (n = 96; weight, 240-250 g) were randomly divided into 3 groups: control, MCT-exposed (MCT), and MCT-exposed plus Gp130 inhibitor (MCT-Gp) administered daily (5 mg/kg) from days 14-28. Eight rats were killed in each group at weeks 1 through 4, with the following measured variables compared across groups on day 28: hemodynamics, right ventricular hypertrophy, morphometric measurements, immunohistochemical results, levels of IL-6, phosphorylated signal transducer and activator of transcription 3, proliferating cell nuclear antigen (PCNA), bone morphogenetic protein receptor-2 (BMPR2), proangiogenic factor, vascular endothelial growth factor (VEGF), proproliferative kinase extracellular signal-regulated kinase (ERK), survivin, Bcl-2, and Bax.
  
  
  
  Compared with the MCT group, Gp130 inhibitor, after MCT exposure, improved hemodynamics and significantly reduced the severity of inflammation, as estimated by levels of IL-6 (P < 0.0001), and reversed pulmonary arterial remodelling, as assessed by medial wall thickness (P < 0.0001). Gp130 inhibitor upregulated BMPR2 expression in MCT-exposed lungs (P = 0.040) and decreased the expression of PCNA, VEGF, ERK, and survivin (all P < 0.05).
  
  
  
  Gp130 inhibitor upregulated BMPR2 expression in MCT-exposed lungs, restored the BMPR2/IL-6 balance, reduced IL-6-associated inflammation, inhibited pulmonary artery smooth muscle cell proliferation, and ameliorated pulmonary vascular remodelling in MCT-induced PH in rats.
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address: zhihongliufuwai@163.com.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Luo
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Yaguo
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Qunying
authors.initials: Q
authors.lastname: Xi
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Tang
mesh_terms: D000818:Animals; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006023:Glycoproteins / Q000037:antagonists & inhibitors*; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D008168:Lung / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D016686:Monocrotaline / Q000633:toxicity; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects / Q000473:pathology; D017207:Rats, Sprague-Dawley; D000077022:Survivin; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C516989:Birc5 protein, rat; D016207:Cytokines; D006023:Glycoproteins; D008869:Microtubule-Associated Proteins; D018809:Proliferating Cell Nuclear Antigen; D000077022:Survivin; D042461:Vascular Endothelial Growth Factor A; C480482:glycoprotein 130, human; D016686:Monocrotaline; D048049:Extracellular Signal-Regulated MAP Kinases; C498220:Bmpr2 protein, rat; D052006:Bone Morphogenetic Protein Receptors, Type II