Anticoagulant heparan sulfate to not clot--or not?
Vascular endothelial cells (ECs) produce anticoagulant heparan sulfate (HSAT+)-a small subpopulation of heparan sulfate (HS) containing a specific pentasaccharide motif with high affinity for plasma antithrombin (AT). This pentasaccharide is responsible for the anticoagulant action of therapeutic heparin, which dramatically catalyzes AT neutralization of coagulation proteases. Consequently, HSAT+ has been designated as "anticoagulant HS," and has long been thought to convey antithrombotic properties to the blood vessel wall. The Hs3st1 gene encodes HS 3-O-sulfotransferase-1, whose rate limiting action regulates EC production of HSAT+. To elucidate the biologic role of HSAT+, we generated Hs3st1-/- knock-out mice that have undetectable EC HSAT+. Despite long held historic expectations, hemostasis was unaffected in Hs3st1-/- mice. In light of this surprising finding, herein we evaluate historic, biochemical, kinetic, physiologic, and molecular genetic studies of AT, heparin, and HSAT+. We find that a hemostatic role for HSAT+ cannot presently be excluded; however, HSAT+ may well not be essential for AT's anticoagulant function. Specifically, in the absence of glycosaminoglycans, physiologic levels of AT can neutralize coagulation proteases at a sufficiently high throughput to account for most of AT's anticoagulant function. Moreover, at the vessel wall surface, glycosaminoglycans distinct from HSAT+ may be the predominant catalysts of AT's anticoagulant activity. We then explore the possibility that HSAT+ regulates a less well known function of AT, anti-inflammatory activity. We find that Hs3st1-/- mice exhibit a strong proinflammatory phenotype that is unresponsive to AT's anti-inflammatory activity. We conclude that the predominant function of HSAT+ is to mediate AT's anti-inflammatory activity.
Shworak
Nicholas W
NW
Department of Medicine, Dartmouth Medical School, Hanover, New Hampshire, USA.
Kobayashi
Takashi
T
de Agostini
Ariane
A
Smits
Nicole C
NC
D000818:Animals; D000925:Anticoagulants / Q000378:metabolism*; D001777:Blood Coagulation; D004730:Endothelium, Vascular / Q000166:cytology* / Q000378:metabolism; D006497:Heparan Sulfate / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D015238:Sulfotransferases / Q000502:physiology*
D000925:Anticoagulants; D006497:Heparan Sulfate; D015238:Sulfotransferases; C021350:heparitin sulfotransferase