HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Effect of Mthfr genotype on diet-induced hyperhomocysteinemia and vascular function in mice

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 M 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. (Blood. 2004;103:2624-2629)