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

Thomas J. Raife, Denis M Dwyre, Jeff W. Stevens, Rochelle A. Erger, Lorie Leo, Katina M. Wilson, Jose A. Fernández, Jennifer Wilder, Hyung Suk Kim, John H. Griffin, Nobuyo Maeda, Steven R. Lentz

Research output: Contribution to journalArticle

8 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2509-2517
Number of pages9
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume31
Issue number11
DOIs
StatePublished - Nov 2011
Externally publishedYes

Keywords

  • atherosclerosis
  • inflammation
  • protein C
  • thrombomodulin
  • thrombosis

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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  • Cite this

    Raife, T. J., Dwyre, D. M., Stevens, J. W., Erger, R. A., Leo, L., Wilson, K. M., Fernández, J. A., Wilder, J., Kim, H. S., Griffin, J. H., Maeda, N., & Lentz, S. R. (2011). Human thrombomodulin knock-in mice reveal differential effects of human thrombomodulin on thrombosis and atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology, 31(11), 2509-2517. https://doi.org/10.1161/ATVBAHA.111.236828