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Hyperhomocysteinemia is associated with increased risk for cardiovascular events, but it is not certain whether it is a mediator of vascular dysfunction or a marker for another risk factor. Homocysteine levels are regulated by folate bioavailability and also by the methyl donor S-adenosylmethionine (SAM) and its metabolite S-adenosylhomocysteine (SAH). We tested the hypotheses that endothelial dysfunction occurs in hyperhomocysteinemic mice in the absence of folate deficiency and that levels of SAM and SAH are altered in mice with dysfunction. Heterozygous cystathionine beta-synthase-deficient (CBS(+/-)) and wild-type (CBS(+/+)) mice were fed a folate-replete, methionine-enriched diet. Plasma levels of total homocysteine were elevated in CBS(+/-) mice compared with CBS(+/+) mice after 7 weeks (27.1+/-5.2 versus 8.8+/-1.1 micromol/L; P&lt;0.001) and 15 weeks (23.9+/-3.0 versus 13.0+/-2.3 micromol/L; P&lt;0.01). After 15 weeks, but not 7 weeks, relaxation of aortic rings to acetylcholine was selectively impaired by 35% (P&lt;0.05) and thrombomodulin anticoagulant activity was decreased by 20% (P&lt;0.05) in CBS(+/-) mice. Plasma levels of folate did not differ between groups. Levels of SAH were elevated approximately 2-fold in liver and brain of CBS(+/-) mice, and correlations were observed between plasma total homocysteine and SAH in liver (r=0.54; P&lt;0.001) and brain (r=0.67; P&lt;0.001). These results indicate that endothelial dysfunction occurs in hyperhomocysteinemic mice even in the absence of folate deficiency. Endothelial dysfunction in CBS(+/-) mice was associated with increased tissue levels of SAH, which suggests that altered SAM-dependent methylation may contribute to vascular dysfunction in hyperhomocysteinemia.

Endothelial Dysfunction and Elevation of S -Adenosylhomocysteine in Cystathionine β-Synthase–Deficient Mice