REGULATION OF PLATELET HEPARANASE DURING INFLAMMATION - ROLE OF PH AND PROTEINASES

Heparan sulfate is rapidly degraded by an endoglycosidase (heparanase) secreted by activated platelets. Since the cleavage and release of he paran sulfate would profoundly alter the local physiology of the endot helium, platelet heparanase activity should be tightly regulated. Cons istent with this hypothesis, platelet heparanase was round to degrade endothelial cell heparan sulfate at pH 6.0 but not at pH 7.4, even tho ugh 25% of maximum activity was detected at pH 7.4. Loss of heparanase activity occurred rapidly (t(1/2) congruent to 20 min) and reversibly at physiologic pH but did not occur at acidic pH (<7.0). inactivation of heparanase at pH 7.4 did not affect heparin binding and was revers ed by 0.5 M NaCl or by heparan sulfate but not by chondroitin sulfate, suggesting inactive heparanase could be tethered on cell surfaces and the function regulated by heparan sulfate. Heparanase was gradually i nactivated by trypsin and urokinase (t(1/2) = 5 h) but resisted cleava ge by leukocyte cathepsin G, leukocyte elastase, plasmin, and thrombin . These findings are consistent with a model in which platelet heparan ase is active at the low pH of inflammation but inactive under physiol ogic conditions preventing inadvertent cleavage of heparan sulfate and loss of physiologic functions of endothelial cells, (C) 1998 Wiley-Li ss, Inc.