title: Factors involved in extracellular matrix turnover in human derived cardiomyocytes.
abstract: BACKGROUND
  The molecular mechanisms by which myocardial ischemia translates into ventricular remodeling remain unclear.
  
  
  METHODS
  We investigated whether hypoxia and proinflammatory cytokines are specific inducers of remodeling signals in an in vitro model of cultured adult human ventricular myocytes (AC16 cells).
  
  
  RESULTS
  Hypoxia modified the ratio of matrix remodeling factors by increasing the aminoterminal propeptide of type III procollagen (PIIINP) and reducing tissue inhibitor of matrix metalloproteinase type 1 (TIMP-1) secretion in AC16 cells. These effects, however, were not associated with either modifications in expression of matrix metalloproteinase type 2, collagen-I or metalloproteinase activity. Hypoxia does, actually increase the production of the cardiac antifibrogenic growth factors, Apelin and VEGF, through an Hypoxia Inducible Factor type 1-dependent mechanism. Concerning proinflammatory signaling pathways, IL1β emerged as a powerful inducer of matrix turnover, since it significantly enhanced PIIINP, TIMP-1 and hyaluronic acid production and increased metalloproteinase activity. In contrast, TNFα did not modify matrix turnover but markedly induced the production of Apelin and VEGF.
  
  
  CONCLUSIONS
  Hypoxia and increased TNFα activity likely exert cardioprotective actions by activating the cardiac antifibrogenic factors Apelin and VEGF. In contrast, IL1β is a strong promoter of interstitial collagen remodeling that may contribute to ventricular dilation and heart failure in the ischemic myocardium.
authors.affiliation: Service of Biochemistry and Molecular Genetics, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Gregori
authors.initials: G
authors.lastname: Casals
authors.forename: Guillermo
authors.initials: G
authors.lastname: Fernández-Varo
authors.forename: Pedro
authors.initials: P
authors.lastname: Melgar-Lesmes
authors.forename: Santi
authors.initials: S
authors.lastname: Marfà
authors.forename: Vedrana
authors.initials: V
authors.lastname: Reichenbach
authors.forename: Manuel
authors.initials: M
authors.lastname: Morales-Ruiz
authors.forename: Wladimiro
authors.initials: W
authors.lastname: Jiménez
mesh_terms: D000073861:Apelin; D015687:Cell Hypoxia / Q000502:physiology; D002478:Cells, Cultured; D024061:Collagen Type III / Q000235:genetics / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: C115436:APLN protein, human; D000073861:Apelin; D024061:Collagen Type III; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins; D053583:Interleukin-1beta; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D014409:Tumor Necrosis Factor-alpha; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D020778:Matrix Metalloproteinase 2