title: Effect of Mthfr genotype on diet-induced hyperhomocysteinemia and vascular function in mice.
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.
authors: Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City 52242, USA.
authors: Angela M
authors: AM
authors: Devlin
authors: Erland
authors: E
authors: Arning
authors: Teodoro
authors: T
authors: Bottiglieri
authors: Frank M
authors: FM
authors: Faraci
authors: Rima
authors: R
authors: Rozen
authors: Steven R
authors: SR
authors: Lentz
mesh_terms: D000818:Animals; D001011:Aorta; D001160:Arterioles / Q000187:drug effects / Q000503:physiopathology; D002536:Cerebral Arteries / Q000187:drug effects / Q000503:physiopathology; D002794:Choline / Q000097:blood; D003433:Crosses, Genetic; D003545:Cysteine / Q000097:blood; D004032:Diet / Q000009:adverse effects*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D005838:Genotype; D020138:Hyperhomocysteinemia / Q000139:chemically induced / Q000235:genetics*; D066298:In Vitro Techniques; D008715:Methionine / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular; D014803:Vitamin B Complex / Q000097:blood
chemical_list: D014803:Vitamin B Complex; D008715:Methionine; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D003545:Cysteine; D002794:Choline