title: Metabolites of Hypoxic Cardiomyocytes Induce the Migration of Cardiac Fibroblasts.
abstract: BACKGROUND
  The migration of cardiac fibroblasts to the infarct region plays a major role in the repair process after myocardial necrosis or damage. However, few studies investigated whether early hypoxia in cardiomyocytes induces the migration of cardiac fibroblasts. The purpose of this study was to assess the role of metabolites of early hypoxic cardiomyocytes in the induction of cardiac fibroblast migration.
  
  
  METHODS
  Neonatal rat heart tissue was digested with a mixture of trypsin and collagenase at an appropriate ratio. Cardiomyocytes and cardiac fibroblasts were cultured via differential adhesion. The cardiomyocyte cultures were subjected to hypoxia for 2, 4, 6, 8, 10, and 12 h. The supernatants of the cardiomyocyte cultures were collected to determine the differences in cardiac fibroblast migration induced by hypoxic cardiomyocyte metabolites at various time points using a Transwell apparatus. Meanwhile, ELISA was performed to measure TNF-α, IL-1β and TGF-β expression levels in the cardiomyocyte metabolites at various time points.
  
  
  RESULTS
  The metabolites of hypoxic cardiomyocytes significantly induced the migration of cardiac fibroblasts. The induction of cardiac fibroblast migration was significantly enhanced by cardiomyocyte metabolites in comparison to the control after 2, 4, and 6 h of hypoxia, and the effect was most significant after 2 h. The expression levels of TNF-α, IL-1β, IL-6, and TGF-β were substantially increased in the metabolites of cardiomyocytes, and neutralization with anti-TNF-α and anti-IL-1β antibodies markedly reduced the induction of cardiac fibroblast migration by the metabolites of hypoxic cardiomyocytes.
  
  
  CONCLUSIONS
  The metabolites of early hypoxic cardiomyocytes can induce the migration of cardiac fibroblasts, and TNF-α and IL-1β may act as the initial chemotactic inducers.
authors.forename: Huairui
authors.initials: H
authors.lastname: Shi
authors.forename: Xuehong
authors.initials: X
authors.lastname: Zhang
authors.forename: Zekun
authors.initials: Z
authors.lastname: He
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Wu
authors.forename: Liya
authors.initials: L
authors.lastname: Rao
authors.forename: Yushu
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D015687:Cell Hypoxia; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D053583:Interleukin-1beta / Q000032:analysis / Q000276:immunology; D015850:Interleukin-6 / Q000032:analysis; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D016212:Transforming Growth Factor beta / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000276:immunology
chemical_list: D057134:Antibodies, Neutralizing; D017077:Culture Media, Conditioned; D053583:Interleukin-1beta; D015850:Interleukin-6; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha
keywords: Cardiac fibroblasts; Cardiomyocytes; Hypoxia; Migration