title: Oversulfated fucoidan and heparin suppress endotoxin induction of plasminogen activator inhibitor-1 in cultured human endothelial cells: their possible mechanism of action.
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 micrograms/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 micrograms/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 beta (IL-1 beta) is a potent inducer of PAI-1 in cultured HUVEC. Heparin, OSF, and its fragments did not suppress the IL-1 beta-induced release of PAI-1 antigen. Treatment of HUVEC with heparitinase or monoclonal antibody against heparin 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.
authors.affiliation: Department of Biochemistry, Faculty of Pharmaceutical Sciences, Fukuoka University, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Soeda
authors.forename: N
authors.initials: N
authors.lastname: Fujii
authors.forename: H
authors.initials: H
authors.lastname: Shimeno
authors.forename: A
authors.initials: A
authors.lastname: Nagamatsu
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000925:Anticoagulants / Q000494:pharmacology*; D002478:Cells, Cultured; D002810:Chondroitinases and Chondroitin Lyases; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D019812:Heparan Sulfate Proteoglycans; D006493:Heparin / Q000494:pharmacology*; D006497:Heparan Sulfate / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors*; D008970:Molecular Weight; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis*; D011133:Polysaccharide-Lyases; D011134:Polysaccharides / Q000737:chemistry / Q000494:pharmacology*; D011509:Proteoglycans / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000911:Antibodies, Monoclonal; D000925:Anticoagulants; D002810:Chondroitinases and Chondroitin Lyases; D019812:Heparan Sulfate Proteoglycans; D006493:Heparin; D006497:Heparan Sulfate; D007375:Interleukin-1; D008070:Lipopolysaccharides; D017395:Plasminogen Activator Inhibitor 1; D011133:Polysaccharide-Lyases; D011134:Polysaccharides; D011509:Proteoglycans; C007789:fucoidan; C021349:heparitinsulfate lyase