title: Proteomic analysis implicates translationally controlled tumor protein as a novel mediator of occlusive vascular remodeling in pulmonary arterial hypertension.
abstract: BACKGROUND
  Pulmonary arterial hypertension (PAH) is a lethal disease characterized by excessive proliferation of pulmonary vascular endothelial cells (ECs). Hereditary PAH (HPAH) is often caused by mutations in the bone morphogenetic protein receptor type 2 gene (BMPR2). However, the mechanisms by which these mutations cause PAH remain unclear. Therefore, we screened for dysregulated proteins in blood-outgrowth ECs of HPAH patients with BMPR2 mutations compared with healthy control subjects.
  
  
  RESULTS
  A total of 416 proteins were detected with 2-dimensional PAGE in combination with liquid chromatography/tandem mass spectrometry analysis, of which 22 exhibited significantly altered abundance in blood-outgrowth ECs from patients with HPAH. One of these proteins, translationally controlled tumor protein (TCTP), was selected for further study because of its well-established role in promoting tumor cell growth and survival. Immunostaining showed marked upregulation of TCTP in lungs from patients with HPAH and idiopathic PAH, associated with remodeled vessels of complex lesions. Increased TCTP expression was also evident in the SU5416 rat model of severe and irreversible PAH, associated with intimal lesions, colocalizing with proliferating ECs and the adventitia of remodeled vessels but not in the vascular media. Furthermore, silencing of TCTP expression increased apoptosis and abrogated the hyperproliferative phenotype of blood-outgrowth ECs from patients with HPAH, raising the possibility that TCTP may be a link in the emergence of apoptosis-resistant, hyperproliferative vascular cells after EC apoptosis.
  
  
  CONCLUSIONS
  Proteomic screening identified TCTP as a novel mediator of endothelial prosurvival and growth signaling in PAH, possibly contributing to occlusive pulmonary vascular remodeling triggered by EC apoptosis.
authors.affiliation: From the Ottawa Hospital Research Institute, Sprott Centre for Stem Cell Research and Regenerative Medicine Program, Ottawa, ON, Canada (J.R.L., C.P.-I., D.W.C., B.J., W.S.F., D.J.S.); University of Ottawa, Faculty of Medicine, Department of Cellular and Molecular Medicine, Ottawa, ON, Canada (J.R.L., W.S.F., D.J.S.); University of Cambridge, Department of Medicine, Addenbrooke's Hospital, Cambridge, UK (M.L.O., E.F., P.C., N.W.M.); and Papworth Hospital, Department of Pathology, Papworth, UK (M.S.).
authors.forename: Jessie R
authors.initials: JR
authors.lastname: Lavoie
authors.affiliation: From the Ottawa Hospital Research Institute, Sprott Centre for Stem Cell Research and Regenerative Medicine Program, Ottawa, ON, Canada (J.R.L., C.P.-I., D.W.C., B.J., W.S.F., D.J.S.); University of Ottawa, Faculty of Medicine, Department of Cellular and Molecular Medicine, Ottawa, ON, Canada (J.R.L., W.S.F., D.J.S.); University of Cambridge, Department of Medicine, Addenbrooke's Hospital, Cambridge, UK (M.L.O., E.F., P.C., N.W.M.); and Papworth Hospital, Department of Pathology, Papworth, UK (M.S.).
authors.forename: Mark L
authors.initials: ML
authors.lastname: Ormiston
authors.affiliation: From the Ottawa Hospital Research Institute, Sprott Centre for Stem Cell Research and Regenerative Medicine Program, Ottawa, ON, Canada (J.R.L., C.P.-I., D.W.C., B.J., W.S.F., D.J.S.); University of Ottawa, Faculty of Medicine, Department of Cellular and Molecular Medicine, Ottawa, ON, Canada (J.R.L., W.S.F., D.J.S.); University of Cambridge, Department of Medicine, Addenbrooke's Hospital, Cambridge, UK (M.L.O., E.F., P.C., N.W.M.); and Papworth Hospital, Department of Pathology, Papworth, UK (M.S.).
authors.forename: Carol
authors.initials: C
authors.lastname: Perez-Iratxeta
authors.affiliation: From the Ottawa Hospital Research Institute, Sprott Centre for Stem Cell Research and Regenerative Medicine Program, Ottawa, ON, Canada (J.R.L., C.P.-I., D.W.C., B.J., W.S.F., D.J.S.); University of Ottawa, Faculty of Medicine, Department of Cellular and Molecular Medicine, Ottawa, ON, Canada (J.R.L., W.S.F., D.J.S.); University of Cambridge, Department of Medicine, Addenbrooke's Hospital, Cambridge, UK (M.L.O., E.F., P.C., N.W.M.); and Papworth Hospital, Department of Pathology, Papworth, UK (M.S.).
authors.forename: David W
authors.initials: DW
authors.lastname: Courtman
authors.affiliation: From the Ottawa Hospital Research Institute, Sprott Centre for Stem Cell Research and Regenerative Medicine Program, Ottawa, ON, Canada (J.R.L., C.P.-I., D.W.C., B.J., W.S.F., D.J.S.); University of Ottawa, Faculty of Medicine, Department of Cellular and Molecular Medicine, Ottawa, ON, Canada (J.R.L., W.S.F., D.J.S.); University of Cambridge, Department of Medicine, Addenbrooke's Hospital, Cambridge, UK (M.L.O., E.F., P.C., N.W.M.); and Papworth Hospital, Department of Pathology, Papworth, UK (M.S.).
authors.forename: Baohua
authors.initials: B
authors.lastname: Jiang
authors.affiliation: From the Ottawa Hospital Research Institute, Sprott Centre for Stem Cell Research and Regenerative Medicine Program, Ottawa, ON, Canada (J.R.L., C.P.-I., D.W.C., B.J., W.S.F., D.J.S.); University of Ottawa, Faculty of Medicine, Department of Cellular and Molecular Medicine, Ottawa, ON, Canada (J.R.L., W.S.F., D.J.S.); University of Cambridge, Department of Medicine, Addenbrooke's Hospital, Cambridge, UK (M.L.O., E.F., P.C., N.W.M.); and Papworth Hospital, Department of Pathology, Papworth, UK (M.S.).
authors.forename: Elisabet
authors.initials: E
authors.lastname: Ferrer
authors.affiliation: From the Ottawa Hospital Research Institute, Sprott Centre for Stem Cell Research and Regenerative Medicine Program, Ottawa, ON, Canada (J.R.L., C.P.-I., D.W.C., B.J., W.S.F., D.J.S.); University of Ottawa, Faculty of Medicine, Department of Cellular and Molecular Medicine, Ottawa, ON, Canada (J.R.L., W.S.F., D.J.S.); University of Cambridge, Department of Medicine, Addenbrooke's Hospital, Cambridge, UK (M.L.O., E.F., P.C., N.W.M.); and Papworth Hospital, Department of Pathology, Papworth, UK (M.S.).
authors.forename: Paola
authors.initials: P
authors.lastname: Caruso
authors.affiliation: From the Ottawa Hospital Research Institute, Sprott Centre for Stem Cell Research and Regenerative Medicine Program, Ottawa, ON, Canada (J.R.L., C.P.-I., D.W.C., B.J., W.S.F., D.J.S.); University of Ottawa, Faculty of Medicine, Department of Cellular and Molecular Medicine, Ottawa, ON, Canada (J.R.L., W.S.F., D.J.S.); University of Cambridge, Department of Medicine, Addenbrooke's Hospital, Cambridge, UK (M.L.O., E.F., P.C., N.W.M.); and Papworth Hospital, Department of Pathology, Papworth, UK (M.S.).
authors.forename: Mark
authors.initials: M
authors.lastname: Southwood
authors.affiliation: From the Ottawa Hospital Research Institute, Sprott Centre for Stem Cell Research and Regenerative Medicine Program, Ottawa, ON, Canada (J.R.L., C.P.-I., D.W.C., B.J., W.S.F., D.J.S.); University of Ottawa, Faculty of Medicine, Department of Cellular and Molecular Medicine, Ottawa, ON, Canada (J.R.L., W.S.F., D.J.S.); University of Cambridge, Department of Medicine, Addenbrooke's Hospital, Cambridge, UK (M.L.O., E.F., P.C., N.W.M.); and Papworth Hospital, Department of Pathology, Papworth, UK (M.S.).
authors.forename: William S
authors.initials: WS
authors.lastname: Foster
authors.affiliation: From the Ottawa Hospital Research Institute, Sprott Centre for Stem Cell Research and Regenerative Medicine Program, Ottawa, ON, Canada (J.R.L., C.P.-I., D.W.C., B.J., W.S.F., D.J.S.); University of Ottawa, Faculty of Medicine, Department of Cellular and Molecular Medicine, Ottawa, ON, Canada (J.R.L., W.S.F., D.J.S.); University of Cambridge, Department of Medicine, Addenbrooke's Hospital, Cambridge, UK (M.L.O., E.F., P.C., N.W.M.); and Papworth Hospital, Department of Pathology, Papworth, UK (M.S.).
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Morrell
authors.affiliation: From the Ottawa Hospital Research Institute, Sprott Centre for Stem Cell Research and Regenerative Medicine Program, Ottawa, ON, Canada (J.R.L., C.P.-I., D.W.C., B.J., W.S.F., D.J.S.); University of Ottawa, Faculty of Medicine, Department of Cellular and Molecular Medicine, Ottawa, ON, Canada (J.R.L., W.S.F., D.J.S.); University of Cambridge, Department of Medicine, Addenbrooke's Hospital, Cambridge, UK (M.L.O., E.F., P.C., N.W.M.); and Papworth Hospital, Department of Pathology, Papworth, UK (M.S.). djstewart@ohri.ca.
authors.forename: Duncan J
authors.initials: DJ
authors.lastname: Stewart
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D014408:Biomarkers, Tumor / Q000502:physiology*; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics; D042783:Endothelial Cells / Q000473:pathology* / Q000502:physiology*; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000175:diagnosis* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D040901:Proteomics / Q000379:methods*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013534:Survival / Q000502:physiology; D000090324:Tumor Protein, Translationally-Controlled 1; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C000715647:TPT1 protein, human; C000715649:Tpt1 protein, rat; D000090324:Tumor Protein, Translationally-Controlled 1; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II
keywords: apoptosis; blood vessels; hypertension, pulmonary; proteomics