Sulfation pattern of the fucose branch is important for the anticoagulant and antithrombotic activities of fucosylated chondroitin sulfates |
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Authors: | Shiguo Chen Guoyun Li Nian Wu Xin Guo Ningbo Liao Xingqian Ye Donghong Liu Changhu Xue Wengang Chai |
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Affiliation: | 1. College of Biosystem Engineering and Food Science, Zhejiang University, Hangzhou 310029, China;2. College of Food Science and Technology, Ocean University of China, Qingdao 266003, China;3. Glycosciences Laboratory, Department of Medicine, Imperial College London, Hammersmith Campus, London W12 0NN, United Kingdom |
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Abstract: | BackgroundThe aim is to compare the structures, anticoagulant and antithrombotic activities of two fucosylated chondroitin sulfates isolated from sea cucumbers Isostichopus badionotus (fCS-Ib) and Pearsonothuria graeffei (fCS-Pg), which were known to have different sulfation patterns on the fucose branches.MethodsThe structures of fCSs were identified using 2D NMR. Anticoagulant activities were measured by activated partial thromboplastin time (APTT) and thrombin time (TT), and inhibition of factors IIa, Xa and XIIa was assessed in vitro. Antithrombotic activity was determined ex vivo by measuring the length and weight of the thrombus generated.ResultsThe two fCSs had identical chondroitin sulfate E backbones and similar fucose branches, but different sulfation patterns of the fucose branches. The fucose branch in fCS-Ib was mainly 2,4-O-sulfated whereas that in fCS-Pg was mainly 3,4-O-sulfated. In vitro assay indicated that fCS-Pg possessed much lower potency than fCS-Ib in prolonging APTT/TT and in inhibition of thrombin. However, they both exhibited similar inhibitory effects on factor X activation by intrinsic tenase complex, and on thrombus generation. Furthermore, both fCSs significantly activated factor XII, which has been proved to be associated with adverse clinical events associated with heparin contaminated by oversulfated chondroitin sulfate.ConclusionThe 2,4-O-sulfated fucose branch is the key structural factor of fCSs for prolonged APTT/TT and inhibition of thrombin, whereas the inhibitory effect of fCSs on factor X, XII activation and thrombus generation was attributed to the overall structure of fCS polysaccharide.General importanceBoth fCSs have well defined structures and can be readily quality-controlled, and therefore may be potential alternatives for heparin as anticoagulant and antithrombotic drugs. |
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Keywords: | fCS, fucosylated chondroitin sulfate Pg, Pearsonothuria graeffei Ib, Isostichopus badionotus CSE, chondroitin sulfate E PMP, 1-phenyl-3-methyl-5-pyrazolone APTT, activated partial thromboplastin time TT, thrombin time PT, prothrombin time Fuc0S, non-sulfated fucose Fuc4S, 4-O-sulfated fucose Fuc2,4S, 2,4-O-disulfated fucose Fuc3,4S, 3,4-O-disulfated fucose FIIa, Factor IIa FXa, Factor Xa FXII, Factor XII AT, Antithrombin HC II, Heparin cofactor II |
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