Enhanced susceptibility to arterial thrombosis in a murine model of hyperhomocysteinemia.

Abstract

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 beta-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 to 8 months to produce graded hyperhomocysteinemia. The time to occlusion of the carotid artery after photochemical injury was shortened by more than 50% in Cbs+/+ or Cbs+/- mice fed the HM/LF diet (P < .001 versus 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 < .05 versus 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.

• Authors: Sanjana Dayal, Katina M Wilson, Lorie Leo, Erland Arning, Teodoro Bottiglieri, Steven R Lentz
• Journal: Blood (Blood) Vol. 108 Issue 7 Pg. 2237-43 (Oct 01 2006) ISSN: 0006-4971 [Print] United States
• PMID: 16804115 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Anticoagulants
• Reactive Oxygen Species
• Nitric Oxide Synthase Type II
• Nitric Oxide Synthase Type III
• Nos3 protein, mouse
• Cystathionine beta-Synthase

Topics

• Animals
• Anticoagulants (metabolism)
• Carotid Arteries (pathology)
• Cystathionine beta-Synthase (genetics)
• Genetic Predisposition to Disease
• Hyperhomocysteinemia (diagnosis, genetics, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Nitric Oxide Synthase Type II (metabolism)
• Nitric Oxide Synthase Type III
• Reactive Oxygen Species
• Thrombosis (pathology)