title: HMGB1 down-regulation mediates terameprocol vascular anti-proliferative effect in experimental pulmonary hypertension.
abstract: Pulmonary arterial hypertension (PAH) is a progressive disease with a poor prognosis. Pulmonary artery smooth muscle cells (PASMCs) play a crucial role in PAH pathophysiology, displaying a hyperproliferative, and apoptotic-resistant phenotype. In the present study, we evaluated the potential therapeutic role of terameprocol (TMP), an inhibitor of cellular proliferation and promoter of apoptosis, in a well-established pre-clinical model of PAH induced by monocrotaline (MCT) and studied the biological pathways modulated by TMP in PASMCs. Wistar rats injected with MCT or saline (SHAM group) were treated with TMP or vehicle. On day 21 after injection, we assessed bi-ventricular hemodynamics and cardiac and pulmonary morphometry. The effects of TMP on PASMCs were studied in a primary culture isolated from SHAM and MCT-treated rats, using an iTRAQ-based proteomic approach to investigate the molecular pathways modulated by this drug. In vivo, TMP significantly reduced pulmonary and cardiac remodeling and improved cardiac function in PAH. In vitro, TMP inhibited proliferation and induced apoptosis of PASMCs. A total of 65 proteins were differentially expressed in PASMCs from MCT rats treated with TMP, some of which involved in the modulation of transforming growth factor beta pathway and DNA transcription. Anti-proliferative effect of TMP seems to be explained, at least in part, by the down-regulation of the transcription factor HMGB1. Our findings support the beneficial role of TMP in PAH and suggest that it may be an effective therapeutic option to be considered in the clinical management of PAH.
authors.affiliation: QOPNA, Departamento de Química, Universidade de Aveiro, Campus Universitário de Santiago, Aveiro, Portugal.|Departamento de Cirurgia e Fisiologia, Faculdade de Medicina, Universidade do Porto, Alameda Professor Hernâni Monteiro, Porto, Portugal.
authors.forename: Rita
authors.initials: R
authors.lastname: Nogueira-Ferreira
authors.affiliation: Departamento de Cirurgia e Fisiologia, Faculdade de Medicina, Universidade do Porto, Alameda Professor Hernâni Monteiro, Porto, Portugal.
authors.forename: Manuel J
authors.initials: MJ
authors.lastname: Ferreira-Pinto
authors.affiliation: Departamento de Cirurgia e Fisiologia, Faculdade de Medicina, Universidade do Porto, Alameda Professor Hernâni Monteiro, Porto, Portugal.
authors.forename: Ana Filipa
authors.initials: AF
authors.lastname: Silva
authors.affiliation: Departamento de Cirurgia e Fisiologia, Faculdade de Medicina, Universidade do Porto, Alameda Professor Hernâni Monteiro, Porto, Portugal.|iBiMED, Departamento de Ciências Médicas, Universidade de Aveiro, Campus Universitário de Santiago, Aveiro, Portugal.
authors.forename: Rui
authors.initials: R
authors.lastname: Vitorino
authors.affiliation: QOPNA, Departamento de Química, Universidade de Aveiro, Campus Universitário de Santiago, Aveiro, Portugal.
authors.forename: Joana
authors.initials: J
authors.lastname: Justino
authors.affiliation: Departamento de Bioquímica, Faculdade de Medicina, Universidade do Porto, Alameda Professor Hernâni Monteiro, Porto, Portugal.
authors.forename: Raquel
authors.initials: R
authors.lastname: Costa
authors.affiliation: Departamento de Cirurgia e Fisiologia, Faculdade de Medicina, Universidade do Porto, Alameda Professor Hernâni Monteiro, Porto, Portugal.|CIAFEL, Faculdade de Desporto, Universidade do Porto, Porto, Portugal.
authors.forename: Daniel
authors.identifier: http://orcid.org/0000-0002-7404-7405
authors.initials: D
authors.lastname: Moreira-Gonçalves
authors.affiliation: Université Bordeaux Segalen, Bordeaux, France.|Inserm, Centre de Recherche Cardio-Thoracique, Bordeaux, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Quignard
authors.affiliation: Université Bordeaux Segalen, Bordeaux, France.|Inserm, Centre de Recherche Cardio-Thoracique, Bordeaux, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ducret
authors.affiliation: Université Bordeaux Segalen, Bordeaux, France.|Inserm, Centre de Recherche Cardio-Thoracique, Bordeaux, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Savineau
authors.affiliation: Departamento de Cirurgia e Fisiologia, Faculdade de Medicina, Universidade do Porto, Alameda Professor Hernâni Monteiro, Porto, Portugal.
authors.forename: Adelino F
authors.initials: AF
authors.lastname: Leite-Moreira
authors.affiliation: QOPNA, Departamento de Química, Universidade de Aveiro, Campus Universitário de Santiago, Aveiro, Portugal.
authors.forename: Rita
authors.initials: R
authors.lastname: Ferreira
authors.affiliation: Departamento de Cirurgia e Fisiologia, Faculdade de Medicina, Universidade do Porto, Alameda Professor Hernâni Monteiro, Porto, Portugal.
authors.forename: Tiago
authors.identifier: http://orcid.org/0000-0003-0193-1467
authors.initials: T
authors.lastname: Henriques-Coelho
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D024243:HMGB1 Protein / Q000378:metabolism*; D006439:Hemodynamics / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009637:Masoprocol / Q000031:analogs & derivatives* / Q000494:pharmacology; D016686:Monocrotaline; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D060066:Protein Interaction Maps; D040901:Proteomics / Q000379:methods; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017208:Rats, Wistar; D020127:Recovery of Function; D013997:Time Factors; D066253:Vascular Remodeling / Q000187:drug effects*; D016277:Ventricular Function, Left / Q000187:drug effects; D016278:Ventricular Function, Right / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D000959:Antihypertensive Agents; D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; C076852:terameprocol; D016686:Monocrotaline; D009637:Masoprocol
keywords: monocrotaline; pulmonary arterial hypertension; terameprocol; vascular remodeling