title: Inhibition of ubiquitin proteasome function prevents monocrotaline-induced pulmonary arterial remodeling.
abstract: OBJECTIVE
  Previous study has indicated that inhibition of proteasome function ameliorates the development of pulmonary arterial hypertension (PAH), while its underlying mechanisms are still unclear. This study was performed to address these issues.
  
  
  METHODS
  Male Sprague-Dawley (SD) rats were divided into five groups: control group, PAH group, vehicle treated PAH group, MG-132 treated PAH group and bortezomib treated PAH group. PAH model was established by a single intraperitoneal injection of monocrotaline (MCT). MG-132 and bortezomib were administered to inhibit proteasome function. The right ventricular systolic pressure (RVSP), the right ventricle hypertrophy index (RVHI) and the percentage of medial wall thickness (%MT) were used to evaluate the development of PAH. Hematoxylin and eosin staining was performed to measure vascular remodeling. Immunoblotting was used to determine Akt phosphorylation, expression of PTEN and NEDD4, and the level of ubiquitinated-PTEN protein.
  
  
  RESULTS
  MCT increased RVSP, RVHI and %MT in rats, while these changes were suppressed by treatment of PAH rats with MG-132 or bortezomib. In PAH model, expression of PTEN was decreased and phosphorylation of Akt was increased, these were accompanied by an elevation of NEDD4 protein level. Treatment of PAH model with MG-132 or bortezomib increased PTEN expression and accumulation of ubiquitinated-PTEN protein and decreased Akt phosphorylation, while didn't change NEDD4 expression.
  
  
  CONCLUSIONS
  Inhibition of proteasome function ameliorates pulmonary arterial remodeling by suppressing UPS-mediated PTEN degradation and subsequent inhibition of PI3K/Akt pathway, indicating that UPS might be a novel target for prevention of PAH.
authors.affiliation: Department of Respiratory Medicine, First Affiliated Hospital of Xi'an JiaoTong University, Xi'an, Shaanxi 710061, People's Republic of China.
authors.forename: Yanting
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Wuhan University of Science and Technology, Wuhan, Hubei 430081, People's Republic of China.
authors.forename: Yinxia
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Respiratory Medicine, First Affiliated Hospital of Xi'an JiaoTong University, Xi'an, Shaanxi 710061, People's Republic of China.
authors.forename: Wenhua
authors.initials: W
authors.lastname: Shi
authors.affiliation: Department of Respiratory Medicine, First Affiliated Hospital of Xi'an JiaoTong University, Xi'an, Shaanxi 710061, People's Republic of China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Respiratory Medicine, First Affiliated Hospital of Xi'an JiaoTong University, Xi'an, Shaanxi 710061, People's Republic of China.
authors.forename: Xin
authors.initials: X
authors.lastname: Yan
authors.affiliation: Department of Respiratory Medicine, First Affiliated Hospital of Xi'an JiaoTong University, Xi'an, Shaanxi 710061, People's Republic of China.
authors.forename: Qingting
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Respiratory Medicine, First Affiliated Hospital of Xi'an JiaoTong University, Xi'an, Shaanxi 710061, People's Republic of China.
authors.forename: Ya
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Respiratory Medicine, First Affiliated Hospital of Xi'an JiaoTong University, Xi'an, Shaanxi 710061, People's Republic of China.
authors.forename: Lan
authors.initials: L
authors.lastname: Yang
authors.affiliation: Division of Allergy and Clinical Immunology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Gao
authors.affiliation: Department of Respiratory Medicine, First Affiliated Hospital of Xi'an JiaoTong University, Xi'an, Shaanxi 710061, People's Republic of China. Electronic address: limx@mail.xjtu.edu.cn.
authors.forename: Manxiang
authors.initials: M
authors.lastname: Li
mesh_terms: D000818:Animals; D000069286:Bortezomib / Q000494:pharmacology*; D056827:Endosomal Sorting Complexes Required for Transport / Q000096:biosynthesis; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D007976:Leupeptins / Q000494:pharmacology*; D008297:Male; D016686:Monocrotaline / Q000633:toxicity*; D000075702:Nedd4 Ubiquitin Protein Ligases; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis; D066253:Vascular Remodeling / Q000187:drug effects*
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D007976:Leupeptins; D061988:Proteasome Inhibitors; D000069286:Bortezomib; D016686:Monocrotaline; C000618479:NEDD4L protein, rat; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618484:Nedd4 protein, rat; D044767:Ubiquitin-Protein Ligases; D051059:PTEN Phosphohydrolase; C487216:Pten protein, rat; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde
keywords: Degradation; NEDD4; PTEN; Pulmonary arterial hypertension; Ubiquitin proteasome system; Vascular remodeling