The relationship between the structure of dermatan sulfate derivatives and their antithrombotic activities

Abstract

To study the relationship between the structure of dermatan sulfate (DS) derivatives and their anti-thrombotic activities, DS-derived oligosaccharides (with different structures and relative molecular weight ( M r)) were prepared, and the effects of the DS-derived oligosaccharides on the activities of heparin cofactor II (HCII), activated protein C (APC), blood platelet, and vascular endothelial cells were studied. The major disaccharides of DS and polysulfated dermatan sulfate (PSDS) were IdoA-1→3-GalNAc-4-OSO 3 and IdoA-2OSO 3-1→3-GalNAc4, 6-diOSO 3, respectively. The results showed that the consequence of the thrombotic inhibitory effects of DS and its derivatives were as follows: PSDS > low molecular weight polysulfated dermatan sulfate (LPSDS) > DS. Both DS and PSDS inhibited platelet aggregation in the concentration-dependent manner, and the IC 50 value of DS and PSDS is 12.7 ± 1.3 and 28.6 ± 0.9 mg/mL, respectively. DS oligosaccharides (DSOSs) and PSDS oligosaccharides (PSDSOSs) both significantly inhibited P-selectin expression on platelet surface ( P < 0.01), while DSOSs have no different effect compared with PSDSOSs. DSOSs and PSDSOSs significantly enhanced the activity of HCII in inhibiting thrombin in the plasma. The most active PSDSOS was PSDSOS 1 with M r of 4959, which enhanced the HCII activity by 91% ( P < 0.01). The experiments on APC activity showed that DS and its derivatives enhanced APC activity. The most active PSDSOS was PSDSOS 3 with M r of 2749, which enhanced the APC activity to 331 ± 27% ( P < 0.01). DSOSs and PSDSOSs enhanced tissue plasminogen activator (t-PA) activity and reduced the plasminogen activator inhibitor (PAI) activity from cultured human umbilical vein endothelial cells (HUVEC), resulting in the ratio of t-PA/PAI going up. PSDSOSs which have the same M r as DSOSs produced more active effects in above assays, except for platelet aggregation.