title: Slug Is Increased in Vascular Remodeling and Induces a Smooth Muscle Cell Proliferative Phenotype.
abstract: OBJECTIVE
  Previous studies have confirmed Slug as a key player in regulating phenotypic changes in several cell models, however, its role in smooth muscle cells (SMC) has never been assessed. The purpose of this study was to evaluate the expression of Slug during the phenotypic switch of SMC in vitro and throughout the development of vascular remodeling.
  
  
  RESULTS
  Slug expression was decreased during both cell-to-cell contact and TGFβ1 induced SMC differentiation. Tumor necrosis factor-α (TNFα), a known inductor of a proliferative/dedifferentiated SMC phenotype, induces the expression of Slug in SMC. Slug knockdown blocked TNFα-induced SMC phenotypic change and significantly reduced both SMC proliferation and migration, while its overexpression blocked the TGFβ1-induced SMC differentiation and induced proliferation and migration. Genome-wide transcriptomic analysis showed that in SMC, Slug knockdown induced changes mainly in genes related to proliferation and migration, indicating that Slug controls these processes in SMC. Notably, Slug expression was significantly up-regulated in lungs of mice using a model of pulmonary hypertension-related vascular remodeling. Highly remodeled human pulmonary arteries also showed an increase of Slug expression compared to less remodeled arteries.
  
  
  CONCLUSIONS
  Slug emerges as a key transcription factor driving SMC towards a proliferative phenotype. The increased Slug expression observed in vivo in highly remodeled arteries of mice and human suggests a role of Slug in the pathogenesis of pulmonary vascular diseases.
authors.affiliation: Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain.
authors.forename: Núria
authors.initials: N
authors.lastname: Coll-Bonfill
authors.affiliation: Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain.|Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Madrid, Spain.
authors.forename: Victor I
authors.initials: VI
authors.lastname: Peinado
authors.affiliation: Instituto de Investigación Médica Mercedes y Martín Ferreyra, INIMEC-CONICET, Universidad Nacional de Córdoba, Córdoba, Argentina.
authors.forename: María V
authors.initials: MV
authors.lastname: Pisano
authors.affiliation: Diabetes and Obesity Laboratory, IDIBAPS, CIBERDEM, Barcelona, Spain.
authors.forename: Marcelina
authors.initials: M
authors.lastname: Párrizas
authors.affiliation: Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Blanco
authors.affiliation: Institute of Functional Genomics, University of Regensburg, Regensburg, Germany.
authors.forename: Maurits
authors.initials: M
authors.lastname: Evers
authors.affiliation: Institute of Functional Genomics, University of Regensburg, Regensburg, Germany.
authors.forename: Julia C
authors.initials: JC
authors.lastname: Engelmann
authors.affiliation: Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain.
authors.forename: Jessica
authors.initials: J
authors.lastname: García-Lucio
authors.affiliation: Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain.|Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Madrid, Spain.
authors.forename: Olga
authors.initials: O
authors.lastname: Tura-Ceide
authors.affiliation: Biochemistry Center Regensburg (BZR), Laboratory for RNA Biology, University of Regensburg, Regensburg, Germany.
authors.forename: Gunter
authors.initials: G
authors.lastname: Meister
authors.affiliation: Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain.|Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Madrid, Spain.
authors.forename: Joan Albert
authors.initials: JA
authors.lastname: Barberà
authors.affiliation: Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain.|Instituto de Investigación Médica Mercedes y Martín Ferreyra, INIMEC-CONICET, Universidad Nacional de Córdoba, Córdoba, Argentina.
authors.forename: Melina M
authors.initials: MM
authors.lastname: Musri
mesh_terms: D000818:Animals; D054337:Cell Dedifferentiation / Q000187:drug effects / Q000235:genetics; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000473:pathology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000378:metabolism*; D010641:Phenotype; D011651:Pulmonary Artery / Q000473:pathology; D000071250:Snail Family Transcription Factors / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D066253:Vascular Remodeling / Q000187:drug effects / Q000235:genetics
chemical_list: D000071250:Snail Family Transcription Factors; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha