GLYCATED PROTEINS MODULATE TISSUE-PLASMINOGEN ACTIVATOR-CATALYZED PLASMINOGEN ACTIVATION

Plasminogen activation by tissue-plasminogen activator (t-PA) is accel erated by the presence of a macromolecular surface, which acts as a te mplate that brings enzyme and substrate in close proximity. Modificati on of lysine residues, which are important for this template function, occurs in diabetic patients as a consequence of glycation of proteins . In this study, we investigated the effects of glycation of fibrin an d other proteins in t-PA-catalyzed plasmin formation. Plasminogen acti vation on glycated fibrin(ogen) was increased compared to non-glycated fibrin(ogen), which could fully be attributed to an increased affinit y of t-PA for glycated fibrin(ogen). Binding of plasminogen to glycate d fibrin was increased, but did not contribute to increased plasminoge n activation. Both plasminogen activator inhibitor-1 (PAI-1) binding a nd activity were increased on glycated fibrin. Induction of template f unction in plasminogen activation was also observed on immobilized gly cated bovine serum albumin (BSA) and human gamma-globulins (IgG). Incr eased plasmin generation at sites of deposition of glycated proteins m ay lead to increased extracellular matrix breakdown and thereby affect the integrity of the endothelial monolayer. Moreover, soluble glycate d BSA and glycated IgG call inhibit t-PA binding to immobilized glycat ed fibrin and interfere with fibrinolysis in diabetic patients. (C) 19 97 Academic Press.