Devlin Angela M, Arning Erland, Bottiglieri Teodoro, Faraci Frank M, Rozen Rima, Lentz Steven R
Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City 52242, USA.
Blood. 2004 Apr 1;103(7):2624-9. doi: 10.1182/blood-2003-09-3078. Epub 2003 Nov 20.
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.
亚甲基四氢叶酸还原酶（MTHFR）缺乏易导致高同型半胱氨酸血症和血管疾病。我们检验了以下假设：Mthfr基因的杂合性破坏使小鼠对饮食诱导的高同型半胱氨酸血症和内皮功能障碍敏感。给Mthfr(+/-)和Mthfr(+/+)小鼠喂食4种饮食中的1种：对照饮食、高蛋氨酸（HM）饮食、低叶酸（LF）饮食或高蛋氨酸/低叶酸（HM/LF）饮食。与对照饮食（P<0.01）或HM饮食（P<0.05）相比，LF和HM/LF饮食组的血浆总同型半胱氨酸（tHcy）更高，且Mthfr(+/-)小鼠的tHcy高于Mthfr(+/+)小鼠（P<0.05）。在对照饮食条件下，Mthfr(+/-)小鼠肝脏和大脑中的S-腺苷甲硫氨酸（SAM）与S-腺苷同型半胱氨酸（SAH）的比值低于Mthfr(+/+)小鼠（P<0.05）。喂食LF或LF/HM饮食的Mthfr(+/+)或Mthfr(+/-)小鼠的SAM/SAH比值进一步降低（P<0.05）。在脑小动脉中，与对照饮食相比，HM/LF饮食使Mthfr(+/+)（最大扩张5%±2%对21%±4%；P<0.01）和Mthfr(+/-)（6%±2%对21%±3%；P<0.01）小鼠对1或10微摩尔乙酰胆碱的内皮依赖性扩张显著且选择性受损。这些发现表明，Mthfr(+/-)基因型使小鼠对饮食诱导的高同型半胱氨酸血症敏感，且高同型半胱氨酸血症会改变组织甲基化能力并损害脑微血管的内皮功能。
