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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. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-09-3078v1 103/7/2624    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Devlin, A. M. Articles by Lentz, S. R. Search for Related Content PubMed PubMed Citation Articles by Devlin, A. M. Articles by Lentz, S. R. Related Collections Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY 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 From the Departments of Internal Medicine and Pharmacology, University of Iowa Carver College of Medicine, Iowa City; Veterans Affairs Medical Center, Iowa City, IA; Baylor Institute of Metabolic Disease, Dallas, TX; and Montreal Children's Hospital Research Institute, McGill University, Montreal, QC, Canada. 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. M. Devlin, R. Singh, R. E. Wade, S. M. Innis, T. Bottiglieri, and S. R. Lentz Hypermethylation of Fads2 and Altered Hepatic Fatty Acid and Phospholipid Metabolism in Mice with Hyperhomocysteinemia J. Biol. Chem., December 21, 2007; 282(51): 37082 - 37090. [Abstract] [Full Text] [PDF] E. Zittan, M. Preis, I. Asmir, A. Cassel, N. Lindenfeld, S. Alroy, D. A. Halon, B. S. Lewis, A. Shiran, J. E. Schliamser, et al. High frequency of vitamin B12 deficiency in asymptomatic individuals homozygous to MTHFR C677T mutation is associated with endothelial dysfunction and homocysteinemia Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H860 - H865. [Abstract] [Full Text] [PDF] K. M. Wilson, R. B. McCaw, L. Leo, E. Arning, S. Lhotak, T. Bottiglieri, R. C. Austin, and S. R. Lentz Prothrombotic Effects of Hyperhomocysteinemia and Hypercholesterolemia in ApoE-Deficient Mice Arterioscler. Thromb. Vasc. Biol., January 1, 2007; 27(1): 233 - 240. [Abstract] [Full Text] [PDF] S. Dayal, K. M. Wilson, L. Leo, E. Arning, T. Bottiglieri, and S. R. Lentz Enhanced susceptibility to arterial thrombosis in a murine model of hyperhomocysteinemia Blood, October 1, 2006; 108(7): 2237 - 2243. [Abstract] [Full Text] [PDF] R. A. Waterland Assessing the Effects of High Methionine Intake on DNA Methylation J. Nutr., June 1, 2006; 136(6): 1706S - 1710S. [Abstract] [Full Text] [PDF] J. Loscalzo Homocysteine Trials -- Clear Outcomes for Complex Reasons N. Engl. J. Med., April 13, 2006; 354(15): 1629 - 1632. [Full Text] [PDF] M. Arenas, G. Simpson, C. M. Lewis, E.-M. Shobowale-Bakre, E. Escuredo, L. D. Fairbanks, J. A. Duley, A. Ansari, J. D. Sanderson, and A. M. Marinaki Genetic Variation in the MTHFR Gene Influences Thiopurine Methyltransferase Activity Clin. Chem., December 1, 2005; 51(12): 2371 - 2374. [Full Text] [PDF] S. Dayal, A. M. Devlin, R. B. McCaw, M.-L. Liu, E. Arning, T. Bottiglieri, B. Shane, F. M. Faraci, and S. R. Lentz Cerebral Vascular Dysfunction in Methionine Synthase-Deficient Mice Circulation, August 2, 2005; 112(5): 737 - 744. [Abstract] [Full Text] [PDF] A. M. Devlin, T. Bottiglieri, F. E. Domann, and S. R. Lentz Tissue-specific Changes in H19 Methylation and Expression in Mice with Hyperhomocysteinemia J. Biol. Chem., July 8, 2005; 280(27): 25506 - 25511. [Abstract] [Full Text] [PDF] S. Dayal and S. R Lentz ADMA and hyperhomocysteinemia Vascular Medicine, May 1, 2005; 10(2_suppl): S27 - S33. [Abstract] [PDF] C. L. Ulrey, L. Liu, L. G. Andrews, and T. O. Tollefsbol The impact of metabolism on DNA methylation Hum. Mol. Genet., April 15, 2005; 14(suppl_1): R139 - R147. [Abstract] [Full Text] [PDF]

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