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J. Biol. Chem., Vol. 277, Issue 11, 8861-8865, March 15, 2002
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From the Department of Molecular and Experimental Medicine, The
Scripps Research Institute, La Jolla, California 92037
To test whether neutral glycosphingolipids can
serve as anticoagulant cofactors, the effects of incorporation of
neutral glycosphingolipids into phospholipid vesicles on anticoagulant
and procoagulant reactions were studied. Glucosylceramide (GlcCer),
lactosylceramide (LacCer), and globotriaosylceramide
(Gb3Cer) in vesicles containing phosphatidylserine (PS) and phosphatidylcholine (PC) dose dependently enhanced factor Va
inactivation by the anticoagulant factors, activated protein C (APC)
and protein S. Addition of GlcCer to PC/PS vesicles enhanced protein
S-dependent APC cleavage in factor Va at Arg-506 by
13-fold, whereas PC/PS vesicles alone minimally affected protein S
enhancement of this reaction. Incorporation into PC/PS vesicles of
GlcCer, LacCer, or Gb3Cer, but not galactosylceramide or
globotetraosylceramide, dose dependently prolonged factor Xa-1-stage
clotting times of normal plasma in the presence of added APC without
affecting baseline clotting times in the absence of APC, showing that
certain neutral glycosphingolipids enhance anticoagulant but not
procoagulant reactions in plasma. Thus, certain neutral
glycosphingolipids (e.g. GlcCer, LacCer, and
Gb3Cer) can enhance anticoagulant activity of APC/protein S
by mechanisms that are distinctly different from those of phospholipids
alone. We speculate that under some circumstances certain neutral
glycosphingolipids either in lipoprotein particles or in cell membranes
may help form antithrombotic microdomains that might enhance
down-regulation of thrombin by APC in vivo.
Neutral Glycosphingolipid-dependent Inactivation of
Coagulation Factor Va by Activated Protein C and Protein S*
*
This work was supported in part by Grants R37HL52246 and
R01HL21544 from the National Institutes of Health and an American Heart
Association Postdoctoral Fellowship (Western States Affiliate) (to
H. D.)The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Molecular and
Experimental Medicine, The Scripps Research Inst., MEM180, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Tel.: 858-784-8220; Fax:
858-784-2243; E-mail: jgriffin@scripps.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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