Heparin Inhibits Activation of Latent Transforming Growth Factor-β1

Aim: Besides acting as an anticoagulant, heparin has antifibrotic effects. Transforming growth factor-beta(1) (TGF-beta(1)) is secreted from cells as latent TGF-beta(1) (LTGF-beta(1)). LTGF-beta(1) consists of TGF-beta(1) and latency-associated peptide (LAP). To be biologically active, TGF-beta(1) has to be released from LAP. Heparin binds to LAP as well as TGF-beta(1) This study was performed to explore the biological effect of the interaction of heparin with LTGF-beta(1). Materials and Methods: TGF-beta(1) was measured by ELISA. Furin-like proprotein convertase activity was assayed using the fluorogenic substrate, Pyr-Arg-Thr-LysArg-AMC. Results: Heparin did not interfere with the receptor binding of TGF-beta(1), but inhibited furin-like proprotein convertase-mediated activation of platelet LTGF-beta(1). 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-beta(1), platelet LTGF-beta(1) and LTGF-beta(1)s secreted in the supernatant of cultured cells. Low-molecular-weight heparins, including dalteparin, enoxaparin and nadroparin, also had inhibitory effects on furin-like proprotein convertasemediated or acid activation of platelet LTGF-beta(1). Conclusion: The findings suggest that heparin renders LTGF-beta(1) resistant to activation, possibly by binding simultaneously to TGF-beta(1) and LAP. Inhibition of LTGF-beta(1) activation by heparin may in part account for its antifibrotic effects. (C) 2013 S. Karger AG, Basel