Effect of Mthfr genotype on diet-induced hyperhomocysteinemia and vascular function in mice

Devlin, Angela M.; Arning, Erland; Bottiglieri, Teodoro; Faraci, Frank M.; Rozen, Rima; Lentz, Steven R.

doi:10.1182/blood-2003-09-3078

Cited by 103 publications

(95 citation statements)

References 39 publications

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“…There is stronger evidence for a direct link between impaired homocysteine metabolism and cerebrovascular disease. Structural and functional vascular changes have been observed in the cerebral arterioles of mice with genetic defects in homocysteine metabolism that were fed diets lacking in folate and high in methionine (6,7). Cerebrovascular abnormalities have also been induced in WT mice and rats with experimental homocysteinemia (8,9).…”

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confidence: 83%

B-vitamin deficiency causes hyperhomocysteinemia and vascular cognitive impairment in mice

Troen

Shea‐Budgell²,

Shukitt‐Hale³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

163

133

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In older adults, mildly elevated plasma total homocysteine (hyperhomocysteinemia) is associated with increased risk of cognitive impairment, cerebrovascular disease, and Alzheimer's disease, but it is uncertain whether this is due to underlying metabolic, neurotoxic, or vascular processes. We report here that feeding male C57BL6/J mice a B-vitamin-deficient diet for 10 weeks induced hyperhomocysteinemia, significantly impaired spatial learning and memory, and caused a significant rarefaction of hippocampal microvasculature without concomitant gliosis and neurodegeneration. Total hippocampal capillary length was inversely correlated with Morris water maze escape latencies (r ‫؍‬ ؊0.757, P < 0.001), and with plasma total homocysteine (r ‫؍‬ ؊0.631, P ‫؍‬ 0.007). Feeding mice a methionine-rich diet produced similar but less pronounced effects. Our findings suggest that cerebral microvascular rarefaction can cause cognitive dysfunction in the absence of or preceding neurodegeneration. Similar microvascular changes may mediate the association of hyperhomocysteinemia with human age-related cognitive decline. cerebrovascular ͉ homocysteine ͉ mouse ͉ nutrition

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mentioning

confidence: 83%

B-vitamin deficiency causes hyperhomocysteinemia and vascular cognitive impairment in mice

Troen

Shea‐Budgell²,

Shukitt‐Hale³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

163

133

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“…[7][8][9][10][11][12] Earlier in vitro studies demonstrated that elevated AdoHcy concentrations and a reduced AdoMet/AdoHcy ratio inhibits DNA methyltransferase reactions in liver 24 and in cultured human fibroblasts. 25 This led to the concept that a lower AdoMet/AdoHcy ratio is an indicator of reduced DNA methylation capacity.…”

Section: Discussionmentioning

confidence: 99%

Tissue-specific relationship of S-adenosylhomocysteine with allele-specificH19/Igf2methylation and imprinting in mice with hyperhomocysteinemia

et al. 2013

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osteoporosis3,4 and depression. 5 The molecular mechanisms contributing to HHcy-related pathologies are not fully known but may involve several pathways including gene-specific changes in DNA methylation. Homocysteine is metabolically-linked to cellular methylation reactions through the methionine cycle. Within the cycle, methionine is converted to S-adenosylmethionine (AdoMet), which serves as a methyl donor for numerous methyl acceptors, including phospholipids, DNA, RNA and proteins. S-adenosylhomocysteine (AdoHcy) is produced as a byproduct of methyl donation, and homocysteine is formed through the DNa methylation is linked to homocysteine metabolism through the generation of S-adenosylmethionine (adoMet) and S-adenosylhomocysteine (adohcy). The ratio of adoMet/adohcy is often considered an indicator of tissue methylation capacity. The goal of this study is to determine the relationship of tissue adoMet and adohcy concentrations to allele-specific methylation and expression of genomically imprinted H19/Igf2. Expression of H19/Igf2 is regulated by a differentially methylated domain (DMD), with H19 paternally imprinted and Igf2 maternally imprinted. F1 hybrid c57BL/6J x Castaneous/EiJ (Cast) mice with (+/-), and without (+/+), heterozygous disruption of cystathionine-β-synthase (Cbs) were fed a control diet or a diet (called hh) to induce hyperhomocysteinemia and changes in tissue adoMet and adohcy. F1 Cast x Cbs +/-mice fed the hh diet had significantly higher plasma total homocysteine concentrations, higher liver adohcy, and lower adoMet/adohcy ratios and this was accompanied by lower liver maternal H19 DMD allele methylation, lower liver Igf2 mRNa levels, and loss of Igf2 maternal imprinting. In contrast, we found no significant differences in adoMet and adohcy in brain between the diet groups but F1 Cast x Cbs +/-mice fed the hh diet had higher maternal H19 DMD methylation and lower H19 mRNa levels in brain. a significant negative relationship between adohcy and maternal H19 DMD allele methylation was found in liver but not in brain. These findings suggest the relationship of adoMet and adohcy to gene-specific DNa methylation is tissue-specific and that changes in DNa methylation can occur without changes in adoMet and adohcy.

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“…Mice were maintained on diets for six-weeks prior to surgery and remained on diets for the duration of the experiment (Table 1). In earlier work FADD has shown to decrease levels total folate in plasma as well as increased plasma homocysteine levels [39,40]. Animals were assigned into groups randomly using a custom written program (Mauselotto) and housed in a temperature (22 ± 2•C), humidity (55 ± 10%), light(12/12 h light/dark cycle) controlled environment.…”

Section: Animal Diets and Experimental Designmentioning

confidence: 99%

Elevated levels of plasma homocysteine, deficiencies in dietary folic acid and uracil–DNA glycosylase impair learning in a mouse model of vascular cognitive impairment

Jadavji

Farr

Lips

et al. 2015

Behavioural Brain Research

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(2015) Elevated levels of plasma homocysteine, deficiencies in dietary folic acid and uracil-DNA glycosylase impair learning in a mouse model of vascular cognitive impairment. Behavioural Brain Research, 283 . pp. 215-226. ISSN 1872-7549 Access from the University of Nottingham repository: http://eprints.nottingham.ac.uk/32983/9/UNG_FADD_20140826_manuscript_final.pdf Copyright and reuse:The Nottingham ePrints service makes this work by researchers of the University of Nottingham available open access under the following conditions. This article is made available under the Creative Commons Attribution Non-commercial No Derivatives licence and may be reused according to the conditions of the licence. For more details see: http://creativecommons.org/licenses/by-nc-nd/2.5/ A note on versions:The version presented here may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher's version. Please see the repository url above for details on accessing the published version and note that access may require a subscription.For more information, please contact eprints@nottingham.ac.uk Elevated levels of plasma homocysteine, deficiencies in dietary folic acid and uracil-DNA glycosylase impair learning in a mouse model of vascular cognitive impairment. ABSTRACTDietary deficiencies in folic acid result in elevated levels of plasma homocysteine, which has been associated with the development of dementia and other neurodegenerative disorders.Previously, we have shown that elevated levels of plasma homocysteine in mice deficient for a DNA repair enzyme, uracil-DNA glycosylase (UNG), result in neurodegeneration. The goal of this study was to evaluate how deficiencies in folic acid and UNG along with elevated levels of homocysteine affect vascular cognitive impairment, via chronic hypoperfusion in an animal model. Ung+/+ and Ung−/− mice were placed on either control (CD) or folic acid deficient (FADD) diets. Six weeks later, the mice either underwent implantation of microcoils around both common carotid arteries. Post-operatively, behavioral tests began at 3-weeks, angiography was measured after 5-weeks using MRI to assess vasculature and at completion of study plasma and brain tissue was collected for analysis. Learning impairments in the Morris water maze (MWM) were observed only in hypoperfused Ung−/− FADD mice and these mice had significantly higher plasma homocysteine concentrations. Interestingly, Ung+/+ FADD produced significant remodeling of the basilar artery and arterial vasculature. Increased expression of GFAP was observed in the dentate gyrus of Ung−/− hypoperfused and FADD sham mice. Chronic hypoperfusion resulted in increased cortical MMP-9 protein levels of FADD hypoperfused mice regardless of genotypes. These results suggest that elevated levels of homocysteine only, as a result of dietary folic acid deficiency, don't lead to memory impairments and neurobiochemical changes. Rather a combination of either chronic hypoperfusion o...

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Effect of Mthfr genotype on diet-induced hyperhomocysteinemia and vascular function in mice

Cited by 103 publications

References 39 publications

B-vitamin deficiency causes hyperhomocysteinemia and vascular cognitive impairment in mice

B-vitamin deficiency causes hyperhomocysteinemia and vascular cognitive impairment in mice

Tissue-specific relationship of S-adenosylhomocysteine with allele-specificH19/Igf2methylation and imprinting in mice with hyperhomocysteinemia

Elevated levels of plasma homocysteine, deficiencies in dietary folic acid and uracil–DNA glycosylase impair learning in a mouse model of vascular cognitive impairment

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