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Blood, 1 April 2004, Vol. 103, No. 7, pp. 2624-2629.
Prepublished online as a Blood First Edition Paper on November 20, 2003; DOI 10.1182/blood-2003-09-3078.
Submitted September 8, 2003
Accepted November 17, 2003
Effect of Mthfr genotype on diet-induced hyperhomocysteinemia and vascular function in mice
Angela M Devlin, Erland Arning, Teodoro Bottiglieri, Frank M Faraci, Rima Rozen, and Steven R Lentz*
Department of Internal Medicine, The University of Iowa Carver College of Medicine, Iowa City, IA, USA; Veterans Affairs Medical Center, Iowa City, IA, USA
Department of Pharmacology, The University of Iowa Carver College of Medicine, Iowa City, IA, USA
Baylor Institute of Metabolic Disease, Dallas, TX, USA
Montreal Children's Hospital Research Institute, McGill University, Montreal, PQ, Canada
* Corresponding author; email: steven-lentz{at}uiowa.edu.
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 one of four 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<0.01) or HM (p<0.05) diets, and Mthfr +/- mice had higher tHcy than Mthfr +/+ mice (p<0.05). 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<0.05). SAM/SAH ratios decreased further in Mthfr +/+ or Mthfr +/- mice fed LF or LF/HM diets (p<0.05). In cerebral arterioles, endothelium-dependent dilatation 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 dilatation 5±2 vs. 21±4%; p<0.01) and Mthfr +/- (6±2 vs. 21±3%; p<0.01) 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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