Submitted February 28, 2006
Accepted May 23, 2006
Enhanced susceptibility to arterial thrombosis
in a murine model of hyperhomocysteinemia
Sanjana Dayal, Katina M Wilson, Lorie Leo, Erland Arning, Teodoro Bottiglieri, and Steven R Lentz*
Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
Baylor Institute of Metabolic Disease, Dallas, Texas, USA
* Corresponding author; email: steven-lentz{at}uiowa.edu.
Hyperhomocysteinemia is a risk factor for thrombosis, but the mechanisms are not well defined. We tested the hypothesis that hyperhomocysteinemia accelerates arterial thrombosis in mice. Mice heterozygous for a targeted disruption of the cystathionine 
-synthase gene (Cbs+/-) and wild type littermates (Cbs+/+) were fed either a control diet or a high methionine/low folate (HM/LF) diet for 6-8 months to produce graded hyperhomocysteinemia. The time to occlusion of the carotid artery after photochemical injury was shortened by >50% in Cbs+/+ or Cbs+/- mice fed the HM/LF diet (P<0.001 vs. control diet). Carotid artery thrombosis was not accelerated in mice deficient in endothelial nitric oxide synthase (Nos3), which suggests that decreased endothelium-derived nitric oxide is not a sufficient mechanism for enhancement of thrombosis. Cbs+/+ and Cbs+/- mice fed the HM/LF diet had elevated levels of reactive oxygen species in the carotid artery, increased aortic expression of the NADPH oxidase catalytic subunit, Nox4, and decreased activation of anticoagulant protein C in the aorta (P<0.05 vs. control diet). We conclude that hyperhomocysteinemia enhances susceptibility to arterial thrombosis through a mechanism that is not caused by loss of endothelium-derived nitric oxide but may involve oxidative stress and impairment of the protein C anticoagulant pathway.
