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  • Title: Effect of Mthfr genotype on diet-induced hyperhomocysteinemia and vascular function in mice.
    Author: Devlin AM, Arning E, Bottiglieri T, Faraci FM, Rozen R, Lentz SR.
    Journal: Blood; 2004 Apr 01; 103(7):2624-9. PubMed ID: 14630804.
    Abstract:
    Deficiency of methylenetetrahydrofolate reductase (MTHFR) predisposes to hyperhomocysteinemia and vascular disease. We tested the hypothesis that heterozygous disruption of the Mthfr gene sensitizes mice to diet-induced hyperhomocysteinemia and endothelial dysfunction. Mthfr(+/-) and Mthfr(+/+) mice were fed 1 of 4 diets: control, high methionine (HM), low folate (LF), or high methionine/low folate (HM/LF). Plasma total homocysteine (tHcy) was higher with the LF and HM/LF diets than the control (P<.01) or HM (P<.05) diets, and Mthfr(+/-) mice had higher tHcy than Mthfr(+/+) mice (P<.05). With the control diet, the S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH) ratio was lower in the liver and brain of Mthfr(+/-) mice than Mthfr(+/+) mice (P<.05). SAM/SAH ratios decreased further in Mthfr(+/+) or Mthfr(+/-) mice fed LF or LF/HM diets (P<.05). In cerebral arterioles, endothelium-dependent dilation to 1 or 10 microM acetylcholine was markedly and selectively impaired with the HM/LF diet compared with the control diet for both Mthfr(+/+) (maximum dilation 5% +/- 2% versus 21% +/- 4%; P<.01) and Mthfr(+/-) (6% +/- 2% versus 21% +/- 3%; P<.01) mice. These findings demonstrate that the Mthfr(+/-) genotype sensitizes mice to diet-induced hyperhomocysteinemia and that hyperhomocysteinemia alters tissue methylation capacity and impairs endothelial function in cerebral microvessels.
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