Effect of Mthfr genotype on diet-induced hyperhomocysteinemia and vascular function in mice
- 1 April 2004
- journal article
- Published by American Society of Hematology in Blood
- Vol. 103 (7), 2624-2629
- https://doi.org/10.1182/blood-2003-09-3078
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 μM 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.Keywords
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