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Structure and contribution to the anti-thrombotic mechanism of dermatan sulfate derivatives

Structure and contribution to the anti-thrombotic mechanism ...

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山东省药学会第一届学术年会

作者： Hai-Yan Du, Sheng-Li Ji (Institute of Biochemical and Biotech Drugs, School of Pharmacy, Shandong University, Jinan 250012, China)

To study the relationship between the structure of Dermatan sulfate (DS) derivatives and their anti-thrombotic mechanism, on the basis of the DS derivatives’ anti-thrombotic activity research, the effects of DS-derived oligosaccharides with different structure and molecular weight on the activities of heparin cofactor ii (HCii), activated protein C (APC), blood platelet and vascular endothelial cells were also studied. The major disaccharides of DS and polysulfated Dermatan sulfate (PSDS) were IdoA-1→3-GalNAc-4-SO3and IdoA-2SO3-l→3-GalNAc4, 6-diSO:t, respectively. The results showed that: The consequence of the thrombotic inhibition effects of DS and its derivatives were as follows: PSDS> LPSDS>DS. DS and PSDS all inhibited platelet aggregation in a concentration-dependent manner with IC50 values of 15.15±3.30, 29.10±3.07, respectively. DS oligosaccharides (DSOSs) and PSDS oligosaccharides (PSDSOSs) all significantly inhibit P-selectin expression on platelet surface (Pii for inhibiting thrombin in the plasma. The most active PSDSOS was PSDSOS, with Mr of 4959, which enhanced the HCii activity to 91%(<0. 01). The experiments on APC activity showed that DS and its derivatives all enhanced APC activity. The most active PSDSOS was PSDSOS3 with M, of 2 749, which enhanced the APC activity to 331.2±27.8% (P<0. 01). DSOSs and PSDSOSs can enhance tissue plasminogen activator (t-PA) activity and reduce the plasminogen activator inhibitor (PAI) activity from cultured human umbilical vein endothelial cells, causing the ratio of t-PA/PAI going up. The most active PSDSOS was PSDSOS, with Mr of 4959. PSDSOSs were more active than DSOSs on the basis of comparable Mr in above activity assay, except for platelet aggregation.

关键词： Dermatan sulfate polysulfated Dermatan sulfate DS oligosaccharides PSDS oligosaccharides anti-thrombotic mechanism, heparin cofactor ii activated protein C tissue plasminogen activator plasminogen activator inhibitor P-selectin, platelet aggregation.

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