Journal article
Human Thrombomodulin Knock-In Mice Reveal Differential Effects of Human Thrombomodulin on Thrombosis and Atherosclerosis
Arteriosclerosis, thrombosis, and vascular biology, Vol.31(11), pp.2509-2517
2011
DOI: 10.1161/ATVBAHA.111.236828
PMID: 21885846
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.
Details
- Title: Subtitle
- Human Thrombomodulin Knock-In Mice Reveal Differential Effects of Human Thrombomodulin on Thrombosis and Atherosclerosis
- Creators
- Thomas J RAIFE - Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, United StatesDenis M DWYRE - Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, United StatesNobuyo MAEDA - Department of Pathology, University of North Carolina, Chapel Hill, NC, United StatesSteven R LENTZ - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, United StatesJeff W STEVENS - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, United StatesRochelle A ERGER - Veterans Affairs Medical Center, Iowa City, IA, United StatesLorie LEO - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, United StatesKatina M WILSON - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, United StatesJose A FERNANDEZ - Department of Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, CA, United StatesJennifer WILDER - Department of Pathology, University of North Carolina, Chapel Hill, NC, United StatesHyung-Suk KIM - Department of Pathology, University of North Carolina, Chapel Hill, NC, United StatesJohn H GRIFFIN - Department of Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, CA, United States
- Resource Type
- Journal article
- Publication Details
- Arteriosclerosis, thrombosis, and vascular biology, Vol.31(11), pp.2509-2517
- DOI
- 10.1161/ATVBAHA.111.236828
- PMID
- 21885846
- NLM abbreviation
- Arterioscler Thromb Vasc Biol
- ISSN
- 1079-5642
- eISSN
- 1524-4636
- Publisher
- Lippincott Williams & Wilkins
- Language
- English
- Date published
- 2011
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984094522702771
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