DEFENSIN MODULATES TISSUE-TYPE PLASMINOGEN-ACTIVATOR AND PLASMINOGEN BINDING TO FIBRIN AND ENDOTHELIAL-CELLS

Defensins are naturally occurring antimicrobial peptides that may part icipate in host defense against microorganisms. We previously reported that the amino acid sequence of leukocyte defensins resembles the lys ine-binding site in the kringles of plasminogen and that defensin inhi bits fibrinolysis mediated by tissue-type plasminogen activator (tPA) and plasminogen. In the present paper we analyze the mechanisms of thi s inhibition. Defensin binds specifically to cultured human umbilical vein endothelial cells (HUVEC) (half maximal binding = 3 mu M) as well as to fibrin. At saturating concentrations (5-10 mu M), defensin stim ulates the maximum binding of plasminogen to HUVEC and to fibrin appro ximately 10-fold. However, defensin inhibits plasminogen binding to bo th surfaces at concentrations >10 mu M. Defensin also inhibits tPA and plasminogen-mediated fibrinolysis in a dose-dependent manner at all c oncentrations tested. Fibrinolysis is almost totally inhibited by 6 mu M defensin, a concentration that stimulates the binding of plasminoge n to fibrin. Discordance between the enhancement of plasminogen bindin g and its activation cannot be explained by an inhibitory effect of de fensin on tPA binding nor by inhibition of plasmin activity, each of w hich occur only at higher concentrations. Rather, these results sugges t that plasminogen bound to fibrin in the presence of defensin is less susceptible to activation by tPA.