Enhanced susceptibility to arterial thrombosis in a murine model of hyperhomocysteinemia.
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.
Dayal
Sanjana
S
Department of Internal Medicine, C32 GH, University of Iowa, Iowa City, IA 52242, USA.
Wilson
Katina M
KM
Leo
Lorie
L
Arning
Erland
E
Bottiglieri
Teodoro
T
Lentz
Steven R
SR
D000818:Animals; D000925:Anticoagulants / Q000378:metabolism; D002339:Carotid Arteries / Q000473:pathology*; D003541:Cystathionine beta-Synthase / Q000235:genetics; D020022:Genetic Predisposition to Disease; D020138:Hyperhomocysteinemia / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D017382:Reactive Oxygen Species; D013927:Thrombosis / Q000473:pathology*
D000925:Anticoagulants; D017382:Reactive Oxygen Species; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D003541:Cystathionine beta-Synthase