Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 27, Issue 1, Pages 233-240Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.ATV.0000251607.96118.af
Keywords
endothelium; homocysteine; thrombosis
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Funding
- NHLBI NIH HHS [HL63943, R01 HL063943, HL62984] Funding Source: Medline
- NINDS NIH HHS [NS24621] Funding Source: Medline
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL063943, P01HL062984] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [P01NS024621] Funding Source: NIH RePORTER
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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 mu mol/L) with the HH or HF/HH diets compared with the control or HF diets (4 to 6 mu mol/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.
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