INHIBITION BY DEXTRAN DERIVATIVES OF FGF-2 PLASMIN-MEDIATED DEGRADATION

In previous work we have shown that some new regenerating agents (RGTA s), molecules which correspond to Some dextran derivatives (DxD) conta ining defined amounts of carboxymethyl (CM), benzylamide (B) and benzy lamide sulfonate (BS) groups, were able to stimulate tissue repair whe n applied at the site of injury. Based on in vitro studies showing tha t these DxD could interact and protect heparin binding growth factors (HBGFs), we postulated that DxD could also act in vivo by protecting e ndogenously released HBGFs against protease degradation. We now presen t data demonstrating that human plasmin (HPl), one of the known protea ses involved in extracellular matrix remodelling and in the local acti vation of some growth factors is specifically inhibited by some specif ic DxD. The most efficient compounds for inhibiting the amidolytic act ivity were substituted by all functions with IC50 at 0.26 mu M for RGT A11 (aDxD obtained from a 40 000 Da dextran containing 110% of CM, 2.5 % of B and 36.5% of BS units and with IC50 at 1.1 mu M for RGTA10 (der ived from 10 000 Da dextran and containing 110% of CM, 0% of B 27.3% o f BS). Compounds which were substituted with only one or two functions were less effective. The degradation of FGF-2 by HPl was analyzed by SDS-concentration of 1 mu M could inhibit by 80-100% FGF-2 degradation induced by HII treatment. In conclusion, the inhibitory activity of s ome DxD towards HPl as well as the ability of these DxD to protect FGF -2 against this proteinase could partially explain its beneficial infl uence on extracellular matrix remodelling following tissue injury.