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Canadian Journal of Cardiology

Glycoprotein 130 Inhibitor Ameliorates Monocrotaline-Induced Pulmonary Hypertension in Rats

  • Zhiwei Huang
    Affiliations
    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
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  • Zhihong Liu
    Correspondence
    Corresponding author: Dr Zhihong Liu, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 167 Beilishi Rd, Xicheng District, Beijing 100037, China. Tel.: +86-010-88398196 or +86-13651276919; fax: +86-010-88396589.
    Affiliations
    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
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  • Qin Luo
    Affiliations
    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
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  • Zhihui Zhao
    Affiliations
    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
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  • Qing Zhao
    Affiliations
    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
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  • Yaguo Zheng
    Affiliations
    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
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  • Qunying Xi
    Affiliations
    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
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  • Yi Tang
    Affiliations
    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
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Published:February 23, 2016DOI:https://doi.org/10.1016/j.cjca.2016.02.058

      Abstract

      Background

      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.

      Methods

      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.

      Results

      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).

      Conclusions

      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.

      Résumé

      Introduction

      L’hypertension artérielle pulmonaire (HAP) est caractérisée par une vasoconstriction, un remodelage vasculaire et des événements microthrombotiques. L’interleukine 6 (IL-6), une cytokine de l’inflammation, peut constituer un facteur essentiel du développement de l’HAP, et la glycoprotéine 130 (Gp130) est une sous-unité importante de transduction du signal de l’IL-6. L’objectif de notre étude était d’évaluer l’efficacité des inhibiteurs de la Gp130 à réduire l’inflammation et à améliorer le remodelage vasculaire associé à l’HAP chez les rats exposés à la monocrotaline (MCT).

      Méthodes

      Nous avons divisé de manière aléatoire les rats Sprague-Dawley (n = 96; poids, 240-250 g) en 3 groupes : le groupe témoin, le groupe des rats exposés à la MCT et le groupe des rats exposés à la MCT qui reçoivent quotidiennement des inhibiteurs de la Gp130 (MCT-Gp) à raison de 5 mg/kg du 14e au 28e jour. Les 8 rats qui étaient abattus dans chaque groupe de la 1re à la 4e semaine, et dont les variables mesurées étaient comparées entre les groupes au 28e jour étaient les suivantes : hémodynamique, hypertrophie ventriculaire droite, mesures morphométriques, résultats immunohistochimiques, concentrations d’IL-6, transducteur de signal phosphorylé et activateur de la transcription 3, antigène nucléaire de prolifération cellulaire (PCNA), récepteur de la protéine morphogénique osseuse de type II (BMPR-II), facteur proangiogénique, facteur de croissance de l’endothélium vasculaire (VEGF), kinases régulées par un signal extracellulaire (ERK), survivine, Bcl-2 et Bax.

      Résultats

      Comparativement au groupe MCT, les inhibiteurs de la Gp130, après l’exposition à la MCT, amélioraient l’hémodynamique et réduisaient significativement l’importance de l’inflammation, selon l’estimation des concentrations d’IL-6 (P < 0,0001), et renversaient le remodelage artériel pulmonaire, selon l’évaluation de l’épaisseur de la paroi médiale (P < 0,0001). Les inhibiteurs de la Gp130 régulaient à la hausse l’expression du BMPR-II dans les poumons exposés à la MCT (P = 0,040) et diminuaient l’expression du PCNA, du VEGF, des ERK et de la survivine (tous P < 0,05).

      Conclusions

      Les inhibiteurs de la Gp130 régulaient à la hausse l’expression du BMPR-II dans les poumons exposés à la MCT, restauraient l’équilibre BMPR-II/IL-6, réduisaient l’inflammation associée à l’IL-6, inhibaient la prolifération des cellules musculaires lisses des artères pulmonaires et amélioraient le remodelage vasculaire pulmonaire associé à l’HAP induite par la MCT chez les rats.
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