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PMID: 12671048 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

Normal levels of anticoagulant heparan sulfate are not essential for normal hemostasis.

The Journal of clinical investigation ·Vol. 111 ·No. 7 ·2003-04-00 ·Pages 989-99

HajMohammadi S, Enjyoji K, Princivalle M, Christi P, Lech M, Beeler D, Rayburn H, Schwartz JJ, Barzegar S, de Agostini AI, Post MJ, Rosenberg RD, Shworak NW

Abstract

Endothelial cell production of anticoagulant heparan sulfate (HS(act)) is controlled by the Hs3st1 gene, which encodes the rate-limiting enzyme heparan sulfate 3-O-sulfotransferase-1 (3-OST-1). In vitro, HS(act) dramatically enhances the neutralization of coagulation proteases by antithrombin. The in vivo role of HS(act) was evaluated by generating Hs3st1(-/-) knockout mice. Hs3st1(-/-) animals were devoid of 3-OST-1 enzyme activity in plasma and tissue extracts. Nulls showed dramatic reductions in tissue levels of HS(act) but maintained wild-type levels of tissue fibrin accumulation under both normoxic and hypoxic conditions. Given that vascular HS(act) predominantly occurs in the subendothelial matrix, mice were subjected to a carotid artery injury assay in which ferric chloride administration induces de-endothelialization and occlusive thrombosis. Hs3st1(-/-) and Hs3st1(+/+) mice yielded indistinguishable occlusion times and comparable levels of thrombin.antithrombin complexes. Thus, Hs3st1(-/-) mice did not show an obvious procoagulant phenotype. Instead, Hs3st1(-/-) mice exhibited genetic background-specific lethality and intrauterine growth retardation, without evidence of a gross coagulopathy. Our results demonstrate that the 3-OST-1 enzyme produces the majority of tissue HS(act). Surprisingly, this bulk of HS(act) is not essential for normal hemostasis in mice. Instead, 3-OST-1-deficient mice exhibited unanticipated phenotypes suggesting that HS(act) or additional 3-OST-1-derived structures may serve alternate biologic roles.

MeSH Terms
Animals Anticoagulants/pharmacology Antithrombins/metabolism Carotid Arteries/pathology Crosses, Genetic Endothelium, Vascular/cytology,enzymology Exons Female Genotype Hemostasis Heparitin Sulfate/pharmacology Male Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Models, Genetic Retroviridae/genetics Sulfotransferases/metabolism Thrombin/metabolism Tissue Distribution
Chemicals
Anticoagulants Antithrombins Heparitin Sulfate Sulfotransferases heparan sulfate D-glucosaminyl 3-O-sulfotransferase Thrombin
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
HajMohammadi Sassan
Section of Cardiology, Department of Medicine, Dartmouth Medical School, Hanover, New Hampshire, USA.
Enjyoji Keiichi
Princivalle Marc
Christi Patricia
Lech Miroslav
Beeler David
Rayburn Helen
Schwartz John J
Barzegar Samad
de Agostini Ariane I
Post Mark J
Rosenberg Robert D
Shworak Nicholas W
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI15809
Published
2003-04-00
Pages
989-99
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC152578
Subset
IM
Grants
NHLBI NIH HHS · P01 HL41484-12 · United States
Corrections
CommentIn
PMID: 12671043
External Links
PubMed source DOI: 10.1172/JCI15809 PMC Full Text View journal details
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