Roles of galactose and sulfate residues in sulfatides for their antagonistic functions in the blood coagulation system.
We previously reported that the sulfatide (galactosylceramide I3-sulfate) may have contradictory functions, namely both coagulant and anticoagulant roles in vivo: sulfatide induced giant thrombi formation when injected into rats with vein ligation, whereas no thrombi were formed when sulfatide was injected into rats without vein ligation. Rather it prolonged bleeding time. To investigate the structural features of sulfatide for both functions, a synthetic sulfatide (galactosylceramide I6-sulfate) which does not occur naturally, cholesterol 3-sulfate and ganglioside GM4 were examined together with naturally occurring sulfatide. Both sulfatides and cholesterol 3-sulfate induced giant thrombi in the rats with vein ligation within ten minutes of injection, although cholesterol 3-sulfate exhibited weaker coagulant activity than the sulfatides. On the contrary, both sulfatides significantly prolonged bleeding time but cholesterol 3-sulfate barely prolonged it when injected without vein ligation. GM4 exhibited neither coagulant nor anticoagulant activity. These results suggested that sulfate moiety in the sulfatides is essential for coagulant activity and that galactose residue enhances the activity, whereas both galactose and sulfate residues seem to be important for anticoagulant activity. This is because the sulfatides possess both residues but GM4 possesses galactose without sulfate and cholesterol 3-sulfate possesses sulfate without galactose. We previously reported that the possible mechanism of anticoagulation by sulfatide was due to its binding to fibrinogen, thereby inhibiting the conversion to fibrin. In this paper we reveal that both sulfatides inhibited thrombin activity independent of heparin cofactor II, thus providing evidence of another anticoagulation mechanism for the sulfatides.
Kyogashima
M
M
Seikagaku Corporation, Central Research Laboratories, 1253 Tateno 3-chome, Higashiyamato-shi, Tokyo 207-0021, Japan. kyogashi@seikagaku.co.jp
Sakai
T
T
Onaya
J
J
Hara
A
A
D000818:Animals; D000925:Anticoagulants / Q000378:metabolism; D001777:Blood Coagulation / Q000187:drug effects; D002122:Calcium Chloride / Q000494:pharmacology; D002417:Cattle; D002784:Cholesterol / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D003029:Coagulants / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005690:Galactose / Q000737:chemistry / Q000378:metabolism*; D005732:Gangliosides / Q000378:metabolism*; D006801:Humans; D008297:Male; D010949:Plasma / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013431:Sulfates / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D013433:Sulfoglycosphingolipids / Q000737:chemistry* / Q000494:pharmacology; D013552:Swine; D013917:Thrombin / Q000378:metabolism; D020246:Venous Thrombosis
D000925:Anticoagulants; D003029:Coagulants; D005732:Gangliosides; D013431:Sulfates; D013433:Sulfoglycosphingolipids; C028253:ganglioside, GM4; D002784:Cholesterol; D013917:Thrombin; D002122:Calcium Chloride; D005690:Galactose