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Am J Physiol Heart Circ Physiol 279: H970-H975, 2000;
0363-6135/00 $5.00
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Vol. 279, Issue 3, H970-H975, September 2000

Folate dependence of hyperhomocysteinemia and vascular dysfunction in cystathionine beta -synthase-deficient mice

Steven R. Lentz1,2, Rochelle A. Erger1, Sanjana Dayal2, Nobuyo Maeda4, M. René Malinow5, Donald D. Heistad1,2,3, and Frank M. Faraci2,3

1 Veterans Affairs Medical Center, Iowa City 52246; Departments of 2 Internal Medicine and 3 Pharmacology, University of Iowa College of Medicine, Iowa City, Iowa 52242; 4 Department of Pathology, University of North Carolina, Chapel Hill, North Carolina 27599; and 5 Oregon Regional Primate Research Center, Beaverton, Oregon 97006

Hyperhomocysteinemia is a risk factor for stroke, myocardial infarction, and venous thrombosis. Moderate hyperhomocysteinemia is associated with impaired endothelial function, but the mechanisms responsible for endothelial dysfunction in hyperhomocysteinemia are poorly understood. We have used genetic and dietary approaches to produce hyperhomocysteinemia in mice. Heterozygous cystathionine beta -synthase-deficient mice (CBS +/-), which have a selective defect in homocysteine transsulfuration, and wild-type (CBS +/+) littermates were fed either a control diet or a diet that is relatively deficient in folic acid for 6 wk. Plasma total homocysteine was 5.3 ± 0.7 µM in CBS +/+ mice and 6.4 ± 0.6 µM in CBS +/- mice (P = 0.3) given the control diet. Plasma total homocysteine was 11.6 ± 4.5 µM in CBS +/+ mice and 25.1 ± 3.2 µM in CBS +/- mice (P = 0.004) given a low-folate diet. In mice fed the control diet, relaxation of aortic rings in response to the endothelium-dependent vasodilator acetylcholine did not differ significantly between CBS +/+ mice and CBS +/- mice. In contrast, in mice fed a low-folate diet, maximal relaxation to acetylcholine was markedly impaired in CBS +/- mice (58 ± 9%) compared with CBS +/+ mice (84 ± 4%) (P = 0.01). No differences in relaxation to the endothelium-independent vasodilator sodium nitroprusside were observed among the four groups of mice. These data indicate that CBS-deficient mice are predisposed to hyperhomocysteinemia during dietary folate deficiency, and moderate hyperhomocysteinemia is associated with marked impairment of endothelial function in mice.

acetylcholine; atherosclerosis; endothelium; homocysteine; thrombomodulin


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