2. Introduction
Heparin cofactor II (HCII) is a ~66 kDa serpin that is highly conserved among vertebrates (1). It inhibits thrombin but not other proteases involved in coagulation or fibrinolysis. Heparin, heparan sulfate, and dermatan sulfate increase the rate of thrombin inhibition by HCII >1000-fold.
The presence of thrombin-HCII complexes in human plasma indicates that HCII inhibits thrombin in vivo (2). Cultured fibroblasts and vascular smooth muscle cells stimulate thrombin inhibition by HCII, but endothelial cells do not, leading to the hypothesis that HCII inhibits thrombin at sites outside the vascular lumen (3).
HCII is present in the intima of normal human arteries (4), and the composition of dermatan sulfate in the arterial wall is altered in atherosclerotic lesions, having reduced HCII-stimulating activity (5). These observations provide circumstantial evidence of a role for HCII as an inhibitor of atherogenesis.
During pregnancy, both the maternal and fetal blood contain trace amounts of a dermatan sulfate proteoglycan that stimulates thrombin inhibition by HCII (6). The placenta is rich in dermatan sulfate and may be the source of this proteoglycan (7). Thus, HCII could be activated locally to inhibit coagulation in the placenta.
Chemotactic peptides are released when HCII is partially degraded by neutrophil proteases (8), suggesting a possible role for HCII in inflammation. HCII could also play a role in wound healing by regulating the mitogenic or chemotactic activities of thrombin (9).
We have generated an HCII knockout mouse that will be useful in elucidating the physiologic function of this protein.
References(1) Colwell NS, Tollefsen DM: Isolation of frog and chicken cDNAs encoding heparin cofactor II. Thromb. Haemost. 80:784-790 (1998)
(2) Liu L, Dewar L, Song Y, Kulczycky M, Blajchman MA, Fenton JW, II, Andrew M, Delorme M, Ginsberg J, Preissner KT, Ofosu FA: Inhibition of thrombin by antithrombin III and heparin cofactor II in vivo. Thromb. Haemost. 73: 405-412 (1994)
(3) McGuire EA, Tollefsen DM: Activation of heparin cofactor II by fibroblasts and vascular smooth muscle cells. J. Biol. Chem. 262: 169-175 (1987)
(4) Cooper ST, Neese LL, DiCuccio MN, Liles DK, Hoffman M, Church FC: Vascular localization of the heparin-binding serpins antithrombin, heparin cofactor II, and protein C inhibitor. Clin. Appl. Thrombosis/Hemostasis 2: 185-191 (1996)
(5) Shirk RA, Parthasarathy N, San Antonio JD, Church FC, Wagner WD: Altered dermatan sulfate structure and reduced heparin cofactor II-stimulating activity of biglycan and decorin from human atherosclerotic plaque. J. Biol. Chem. 275: 18085-18092 (2000)
(6) Andrew M, Mitchell L, Berry L, Paes B, Delorme M, Ofosu F, Burrows R, Khambalia B: An anticoagulant dermatan sulfate proteoglycan circulates in the pregnant woman and her fetus. J. Clin. Invest. 89: 321-326 (1992)
(7) Brennan MJ, Oldberg A, Pierschbacher MD, Ruoslahti E: Chondroitin/dermatan sulfate proteoglycan in human fetal membranes: demonstration of an antigenically similar proteoglycan in fibroblasts. J. Biol. Chem. 259: 13742-13750 (1984)
(8) Church FC, Pratt CW, Hoffman M: Leukocyte chemoattractant peptides from the serpin heparin cofactor II. J. Biol. Chem. 266: 704-709 (1991)
(9) Coughlin SR, Vu T-KH, Hung DT, Wheaton VI: Characterization of a functional thrombin receptor. Issues and opportunities. J. Clin. Invest. 89: 351-355 (1992)