Heparin inhibits activation of latent transforming growth factor-β1

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.

TGF-β1 was measured by ELISA. Furin-like proprotein convertase activity was assayed using the fluorogenic substrate, Pyr-Arg-Thr-Lys-Arg-AMC.

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.

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.