Heparin inhibits activation of latent transforming growth factor-ß1.

ABSTRACT

AIM: Besides acting as an anticoagulant, heparin has antifibrotic effects. Transforming growth factor-ß1 (TGF-ß1) is secreted from cells as latent TGF-ß1 (LTGF-ß1). LTGF-ß1 consists of TGF-ß1 and latency-associated peptide (LAP). To be biologically active, TGF-ß1 has to be released from LAP. Heparin binds to LAP as well as TGF-ß1. This study was performed to explore the biological effect of the interaction of heparin with LTGF-ß1. MATERIALS AND METHODS: TGF-ß1 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-ß1, but inhibited furin-like proprotein convertase-mediated activation of platelet LTGF-ß1. 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-ß1, platelet LTGF-ß1 and LTGF-ß1s 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-ß1. CONCLUSION: The findings suggest that heparin renders LTGF-ß1 resistant to activation, possibly by binding simultaneously to TGF-ß1 and LAP. Inhibition of LTGF-ß1 activation by heparin may in part account for its antifibrotic effects.