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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:233.)
© 2007 American Heart Association, Inc.

Thrombosis

Prothrombotic Effects of Hyperhomocysteinemia and Hypercholesterolemia in ApoE-Deficient Mice

Katina M. Wilson; Ryan B. McCaw; Lorie Leo; Erland Arning; árka Lhoták; Teodoro Bottiglieri; Richard C. Austin; Steven R. Lentz

From the Department of Internal Medicine (K.M.W., R.B.M., L.L., S.R.L.), The University of Iowa Carver College of Medicine, Iowa City; Baylor Institute of Metabolic Disease (E.A., T.B.), Dallas, Tex; McMaster University (S.L., R.C.A.), Hamilton, Ontario; and the Veterans Affairs Medical Center (S.R.L.), Iowa City Iowa.

Correspondence to Steven R. Lentz, MD, PhD, Department of Internal Medicine, C32 GH, The University of Iowa, Iowa City, IA 52242. E-mail steven-lentz{at}uiowa.edu

Objective— We tested the hypothesis that hyperhomocysteinemia and hypercholesterolemia promote arterial thrombosis in mice.

Methods and Results— Male apolipoprotein E (Apoe)-deficient mice were fed one of four diets: control, hyperhomocysteinemic (HH), high fat (HF), or high fat/hyperhomocysteinemic (HF/HH). Total cholesterol was elevated 2-fold with the HF or HF/HH diets compared with the control or HH diets (P<0.001). Plasma total homocysteine (tHcy) was elevated (12 to 15 µmol/L) with the HH or HF/HH diets compared with the control or HF diets (4 to 6 µmol/L; P<0.001). Aortic sinus lesion area correlated strongly with total cholesterol (P<0.001) but was independent of tHcy. At 12 weeks of age, the time to thrombotic occlusion of the carotid artery after photochemical injury was >50% shorter in mice fed the HF diets, with or without hyperhomocysteinemia, compared with the control diet (P<0.05). At 24 weeks of age, carotid artery thrombosis was also accelerated in mice fed the HH diet (P<0.05). Endothelium-dependent nitric oxide–mediated relaxation of carotid artery rings was impaired in mice fed the HF, HH, or HF/HH diets compared with the control diet (P<0.05).

Conclusions— Hyperhomocysteinemia and hypercholesterolemia, alone or in combination, produce endothelial dysfunction and increased susceptibility to thrombosis in Apoe-deficient mice.

We tested the hypothesis that hyperhomocysteinemia and hypercholesterolemia promote thrombosis. Carotid artery thrombosis was accelerated and endothelium-dependent relaxation of carotid artery rings was impaired in apolipoprotein E-deficient mice fed either high fat or hyperhomocysteinemic diets. We conclude that hyperhomocysteinemia and hypercholesterolemia produce endothelial dysfunction and increased susceptibility to arterial thrombosis.

Key Words: endothelium • homocysteine • thrombosis

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