title: Suppression of transient receptor potential melastatin 4 expression promotes conversion of endothelial cells into fibroblasts via transforming growth factor/activin receptor-like kinase 5 pathway.
abstract: OBJECTIVE
  To study whether transient receptor potential melastatin 4 (TRPM4) participates in endothelial fibrosis and to investigate the underlying mechanism.
  
  
  METHODS
  Primary human endothelial cells were used and pharmacological and short interfering RNA-based approaches were used to test the transforming growth factor beta (TGF-β)/activin receptor-like kinase 5 (ALK5) pathway participation and contribution of TRPM7 ion channel.
  
  
  RESULTS
  Suppression of TRPM4 expression leads to decreased endothelial protein expression and increased expression of fibrotic and extracellular matrix markers. Furthermore, TRPM4 downregulation increases intracellular Ca levels as a potential condition for fibrosis. The underlying mechanism of endothelial fibrosis shows that inhibition of TRPM4 expression induces TGF-β1 and TGF-β2 expression, which act through their receptor, ALK5, and the nuclear translocation of the profibrotic transcription factor smad4.
  
  
  CONCLUSIONS
  TRPM4 acts to maintain endothelial features and its loss promotes fibrotic conversion via TGF-β production. The regulation of TRPM4 levels could be a target for preserving endothelial function during inflammatory diseases.
authors.affiliation: aLaboratorio de Fisiopatología Integrativa, Departamento de Ciencias Biologicas, Facultad de Ciencias Biologicas, Facultad de Medicina, Universidad Andres Bello bInstituto de Ciencias Biomedicas, Facultad de Medicina, Universidad de Chile cLaboratorio de Bionanotecnologia, Universidad Bernardo O'Higgins dLaboratorio de Biología y Fisiopatología Molecular, Departamento de Ciencias Biologicas, Facultad de Ciencias Biologicas, Facultad de Medicina, Universidad Andres Bello eCentro de Investigacion y Tratamiento del Cancer fCentro de Estudios Moleculares de la Celula gMillennium Institute on Immunology and Immunotherapy, Santiago, Republic of Chile.
authors.forename: Cesar
authors.initials: C
authors.lastname: Echeverría
authors.forename: Ignacio
authors.initials: I
authors.lastname: Montorfano
authors.forename: Claudio
authors.initials: C
authors.lastname: Cabello-Verrugio
authors.forename: Ricardo
authors.initials: R
authors.lastname: Armisén
authors.forename: Diego
authors.initials: D
authors.lastname: Varela
authors.forename: Felipe
authors.initials: F
authors.lastname: Simon
mesh_terms: D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis / Q000235:genetics*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D050053:TRPM Cation Channels / Q000235:genetics* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D053781:Transforming Growth Factor beta2 / Q000378:metabolism*
chemical_list: D018125:Receptors, Transforming Growth Factor beta; C508960:TGFB1 protein, human; C509041:TGFB2 protein, human; D050053:TRPM Cation Channels; C437888:TRPM4 protein, human; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; D017346:Protein Serine-Threonine Kinases; C486583:TRPM7 protein, human; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human; D002118:Calcium