title: Osteoprotegerin Disruption Attenuates HySu-Induced Pulmonary Hypertension Through Integrin αvβ3/FAK/AKT Pathway Suppression.
abstract: BACKGROUND
  Pulmonary arterial remodeling characterized by increased vascular smooth muscle proliferation is commonly seen in life-threatening disease, pulmonary arterial hypertension (PAH). Clinical studies have suggested a correlation between osteoprotegerin serum levels and PAH severity. Here, we aimed to invhestigate vascular osteoprotegerin expression and its effects on pulmonary arterial smooth muscle cell proliferation in vitro and in vivo, as well as examine the signal transduction pathways mediating its activity.
  
  
  RESULTS
  Serum osteoprotegerin levels were significantly elevated in patients with PAH and correlated with disease severity as determined by the World Health Organization (WHO) functional classifications and 6-minute walking distance tests. Similarly, increased osteoprotegerin expression was observed in the pulmonary arteries of hypoxia plus SU5416- and monocrotaline-induced PAH animal models. Moreover, osteoprotegerin disruption attenuated hypoxia plus SU5416-induced PAH progression by reducing pulmonary vascular remodeling, whereas lentiviral osteoprotegerin reconstitution exacerbated PAH by increasing pulmonary arterial smooth muscle cell proliferation. Furthermore, pathway analysis revealed that osteoprotegerin induced pulmonary arterial smooth muscle cell proliferation by interacting with integrin αvβ3to elicit downstream focal adhesion kinase and AKT pathway activation.
  
  
  CONCLUSIONS
  Osteoprotegerin facilitates PAH pathogenesis by regulating pulmonary arterial smooth muscle cell proliferation, suggesting that it may be a potential biomarker and therapeutic target in this disease.
authors.affiliation: From the Department of Cardiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Daile
authors.initials: D
authors.lastname: Jia
authors.affiliation: From the Department of Cardiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhu
authors.affiliation: From the Department of Cardiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Liu
authors.affiliation: From the Department of Cardiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Caojian
authors.initials: C
authors.lastname: Zuo
authors.affiliation: From the Department of Cardiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Yuhu
authors.initials: Y
authors.lastname: He
authors.affiliation: From the Department of Cardiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Guilin
authors.initials: G
authors.lastname: Chen
authors.affiliation: From the Department of Cardiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. lvankang@medmail.com.cn.
authors.forename: Ankang
authors.initials: A
authors.lastname: Lu
mesh_terms: D000818:Animals; D062186:Arterial Pressure; D016022:Case-Control Studies; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*; D000860:Hypoxia / Q000150:complications*; D007211:Indoles; D039302:Integrin alphaVbeta3 / Q000235:genetics / Q000378:metabolism; D008297:Male; D018345:Mice, Knockout; D008875:Middle Aged; D016686:Monocrotaline; D009131:Muscle, Smooth, Vascular / Q000201:enzymology* / Q000503:physiopathology; D053244:Osteoprotegerin / Q000097:blood / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011651:Pulmonary Artery / Q000201:enzymology / Q000503:physiopathology; D011758:Pyrroles; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D015398:Signal Transduction; D014162:Transfection; D066253:Vascular Remodeling; D000070857:Walk Test
chemical_list: D007211:Indoles; D039302:Integrin alphaVbeta3; D053244:Osteoprotegerin; D011758:Pyrroles; C506030:TNFRSF11B protein, human; C506031:Tnfrsf11b protein, mouse; C116890:Semaxinib; D016686:Monocrotaline; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; C496051:Ptk2 protein, mouse; D051057:Proto-Oncogene Proteins c-akt
keywords: biomarkers; cell proliferation; osteoprotegerin; pulmonary hypertension; pulmonary vascular smooth muscle cells