Antithrombotic activity of dermatan sulfate in heparin cofactor II-deficient mice.
Heparin cofactor II (HCII) is a plasma protein that inhibits thrombin rapidly in the presence of dermatan sulfate or heparin. We previously reported that the time to thrombotic occlusion of the carotid artery after photochemical injury was shorter in HCII-deficient mice than in wild-type control animals. In this paper, we describe the antithrombotic activity of dermatan sulfate in wild-type and HCII-deficient mice. Intravenous administration of porcine skin dermatan sulfate induced a dose-dependent prolongation of the carotid artery occlusion time in HCII(+/+) mice that was not observed in HCII(-/-) animals. Pharmacokinetic studies suggested that porcine skin dermatan sulfate expresses antithrombotic activity after being transferred from the plasma to sites in the vessel wall. Using invertebrate dermatan sulfate preparations, we showed that N-acetylgalactosamine-4-O-sulfate residues are required for the HCII-dependent antithrombotic effect. Furthermore, the invertebrate dermatan sulfates, which have higher charge densities than mammalian dermatan sulfate, slightly prolonged the thrombotic occlusion time of HCII(-/-) mice. These results indicate that HCII mediates the antithrombotic effect of porcine skin dermatan sulfate after injury to the carotid arterial endothelium in mice, whereas more highly charged dermatan sulfates possess weak antithrombotic activity independent of HCII.
Department of Medicine, Washington University School of Medicine, 660 South Euclid Ave, St Louis, MO 63110, USA.
Cristina P
CP
Vicente
Li
L
He
Mauro S G
MS
Pavão
Douglas M
DM
Tollefsen
D000818:Animals; D000991:Antithrombins / Q000494:pharmacology*; D002341:Carotid Artery Thrombosis / Q000188:drug therapy; D003871:Dermatan Sulfate / Q000493:pharmacokinetics / Q000494:pharmacology*; D004195:Disease Models, Animal; D015844:Heparin Cofactor II / Q000172:deficiency* / Q000235:genetics / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D011995:Recombination, Genetic; D012867:Skin / Q000378:metabolism; D013552:Swine
D000991:Antithrombins; D003871:Dermatan Sulfate; D015844:Heparin Cofactor II