title: Heparin inhibits activation of latent transforming growth factor-β1.
abstract: OBJECTIVE
  Besides acting as an anticoagulant, heparin has antifibrotic effects. Transforming growth factor-β1 (TGF-β1) is secreted from cells as latent TGF-β1 (LTGF-β1). LTGF-β1 consists of TGF-β1 and latency-associated peptide (LAP). To be biologically active, TGF-β1 has to be released from LAP. Heparin binds to LAP as well as TGF-β1. This study was performed to explore the biological effect of the interaction of heparin with LTGF-β1.
  
  
  METHODS
  TGF-β1 was measured by ELISA. Furin-like proprotein convertase activity was assayed using the fluorogenic substrate, Pyr-Arg-Thr-Lys-Arg-AMC.
  
  
  RESULTS
  Heparin did not interfere with the receptor binding of TGF-β1, but inhibited furin-like proprotein convertase-mediated activation of platelet LTGF-β1. This was not by inhibition of the enzyme because heparin did not inhibit the activity of furin-like proprotein convertase. In addition, heparin inhibited acid activations of recombinant small LTGF-β1, platelet LTGF-β1 and LTGF-β1s secreted in the supernatant of cultured cells. Low-molecular-weight heparins, including dalteparin, enoxaparin and nadroparin, also had inhibitory effects on furin-like proprotein convertase-mediated or acid activation of platelet LTGF-β1.
  
  
  CONCLUSIONS
  The findings suggest that heparin renders LTGF-β1 resistant to activation, possibly by binding simultaneously to TGF-β1 and LAP. Inhibition of LTGF-β1 activation by heparin may in part account for its antifibrotic effects.
authors.affiliation: Department of Pediatrics, College of Medicine, Dankook University, Cheonan, Korea.
authors.forename: Mee Jeong
authors.initials: MJ
authors.lastname: Lee
mesh_terms: D000328:Adult; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D045683:Furin / Q000378:metabolism; D006493:Heparin / Q000494:pharmacology*; D006495:Heparin, Low-Molecular-Weight / Q000494:pharmacology; D006801:Humans; D053779:Latent TGF-beta Binding Proteins / Q000187:drug effects* / Q000378:metabolism; D015539:Platelet Activation / Q000187:drug effects; D043484:Proprotein Convertases / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D005343:Fibrinolytic Agents; D006495:Heparin, Low-Molecular-Weight; C509032:LTBP1 protein, human; D053779:Latent TGF-beta Binding Proteins; D053773:Transforming Growth Factor beta1; D006493:Heparin; D043484:Proprotein Convertases; D045683:Furin