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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:1713.)
© 2003 American Heart Association, Inc.

Editorials

Atherosclerosis

Testing the Water

Enrico Di Cera

From the Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Mo.

Correspondence to Enrico Di Cera, Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110.E-mail enrico@biochem.wustl.edu

An extract of the first 250 words of the full text is provided, because this article has no abstract.

Acritical regulatory pathway of the blood coagulation cascade is provided by antithrombin, a serine protease inhibitor (serpin) that specifically shuts down the activity of factor Xa and thrombin.¹ Much of what we know about the mechanisms of antithrombin function has come from studies using the cofactor heparin, that allosterically activates antithrombin for optimal presentation to the target protease.^1,2 In the case of factor Xa, this activation is sufficient for neutralization of enzyme function.² The heparin-assisted activation of antithrombin is of clinical relevance as heparinoids retain center stage in anticoagulant therapy.³ However, the extracellular environment in which antithrombin functions in vivo is populated by a variety of glycosaminoglycans (GAGs) like heparin sulfate, dermatan sulfate and chondroitin sulfate (CS). GAGs have anticoagulant activity, but they often lack the heparin pentasaccharide unit required for antithrombin activation, which has raised important questions about their precise mechanism of action.

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In the extracellular matrix, GAGs are anchored to proteoglycans and feature different degrees of sulfation that can affect both ion distribution and the water content of the environment. Versican is the most abundant proteoglycan present in the arteries and uses long chains of CS as GAG appendices. Because of the ionic nature of GAGs and their spatial arrangement in the extracellular matrix, several possible mechanisms may be at the basis of their anticoagulant activity. Electrostatic forces generated by the sulfated components of GAGs may steer antithrombin and target proteases to facilitate productive collision. Furthermore, the spatial arrangement of the long GAG chains may . . . [Full Text of this Article]