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Arterioscler Thromb Vasc Biol. 2011 Nov;31(11):2509-17. doi: 10.1161/ATVBAHA.111.236828.

Human thrombomodulin knock-in mice reveal differential effects of human thrombomodulin on thrombosis and atherosclerosis.

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  • 1Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, USA.

Abstract

OBJECTIVE:

We sought to develop a murine model to examine the antithrombotic and antiinflammatory functions of human thrombomodulin in vivo.

METHODS AND RESULTS:

Knock-in mice that express human thrombomodulin from the murine thrombomodulin gene locus were generated. Compared with wild-type mice, human thrombomodulin knock-in mice exhibited decreased protein C activation in the aorta (P<0.01) and lung (P<0.001). Activation of endogenous protein C following infusion of thrombin was decreased by 90% in knock-in mice compared with wild-type mice (P<0.05). Carotid artery thrombosis induced by photochemical injury occurred more rapidly in knock-in mice (12±3 minutes) than in wild-type mice (31±6 minutes; P<0.05). No differences in serum cytokine levels were detected between knock-in and wild-type mice after injection of endotoxin. When crossed with apolipoprotein E-deficient mice and fed a Western diet, knock-in mice had a further decrease in protein C activation but did not exhibit increased atherosclerosis.

CONCLUSION:

Expression of human thrombomodulin in place of murine thrombomodulin produces viable mice with a prothrombotic phenotype but unaltered responses to systemic inflammatory or atherogenic stimuli. This humanized animal model will be useful for investigating the function of human thrombomodulin under pathophysiological conditions in vivo.

PMID:
21885846
[PubMed - indexed for MEDLINE]
PMCID:
PMC3202707
Free PMC Article

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