Abstract

Plasminogen activator inhibitor-1 (PAI-1) is a primary endogenous inhibitor of tissue-type plasminogen activator (t-PA). In this study, we examined the effects of oversulfated fucoidan (OSF) derivatives and heparin on lipopolysaccharide (LPS)-induced release of PAI-1 antigen from cultured human umbilical vein endothelial cells (HUVEC). Addition of LPS (10 μg/ml) enhanced the release of PAI-1 by HUVEC but not of t-PA antigen. At 18 h, a 2.4-fold increase in the extracellular PAI-1 level was observed. The increased PAI-1 level was reduced to control level by the simultaneous addition of 10 μg/ml of OSF or heparin. The suppressive effect of native fucoidan was negligible. We also examined the molecular size effect of OSF, using 10–20, 20–40, and 40–60 kDa fragments. The result indicated that these fragments were effective as well as the 100–130 kDa form of OSF, hence suggesting an important role of the degree of sulfation. Interleukin-1 β (IL-1β) is a potent inducer of PAI-1 in cultured HUVEC. Heparin, OSF, and its fragments did not suppress the IL-1 β-induced release of PAI-l antigen. Treatment of HUVEC with heparitinase or monoclonal antibody against heparan sulfate proteoglycan (HSPG) resulted in a complete loss of its ability to enhance PAI-1 release in response to LPS stimulation, while the chondroitinase ABC treatment hardly affected the PAI-1 production. These results suggest that HSPG is involved in the initial binding of LPS to HUVEC. The suppressive effects of OSF and heparin on LPS-induced PAI-1 release may result from the inhibition of LPS binding to the cell surface HSPG.

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