Endothelial Dysfunction and Elevation of
            <i>S</i>
            -Adenosylhomocysteine in Cystathionine β-Synthase–Deficient Mice

Dayal, Sanjana; Bottiglieri, Teodoro; Arning, Erland; Maeda, Nobuyo; Malinow, M. R.; Sigmund, Curt D.; Heistad, Donald D.; Faraci, Frank M.; Lentz, Steven R.

doi:10.1161/hh1101.092180

Cited by 197 publications

(181 citation statements)

References 53 publications

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“…[AdoHcy] ratio in this tissue (7). In the severely hyperhomocyst(e)inemic Cbs mutant homozygote, AdoMet levels in liver are elevated approximately 2-fold, while AdoHcy levels are elevated about 9-fold, again resulting in a reduced AdoMet:AdoHcy ratio and impaired genomic DNA methylation status (8).…”

Section: Cystathionine β-Synthasementioning

confidence: 96%

Defects in homocysteine metabolism: diversity among hyperhomocyst(e)inemias

Matthews

Elmore

2007

Clinical Chemical Laboratory Medicine

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There are now four genetic mouse models that induce hyperhomocyst(e)inemia by decreasing the activity of an enzyme involved in homocysteine metabolism: cystathionine β-synthase, methylenetetrahydrofolate reductase, methionine synthase and methionine synthase reductase. While each enzyme deficiency leads to murine hyperhomocyst(e)inemia, the accompanying metabolic profiles are significantly and often unexpectedly, different. Deficiencies in cystathionine β-synthase lead to elevated plasma methionine, while deficiencies of the remaining three enzymes lead to hypomethioninemia. The liver [S-adenosylmethionine]:[S-adenosylhomocysteine] ratio is decreased in mice lacking methylenetetrahydrofolate reductase or cystathionine β-synthase, but unexpectedly increased in mice with deficiencies in methionine synthase or methionine synthase reductase. Folate pool imbalances are seen in complete methylenetetrahydrofolate reductase deficiency, where methyltetrahydrofolate is a minor component, and in methionine synthase reductase deficiency, where methyltetrahydrofolate is increased relative to wild-type mice. These differences illustrate the potential diversity among human patients with hyperhomocyst(e)inemia, and strengthen the argument that the pathologies associated with the dissimilar forms of the condition will require different treatments.

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Section: Cystathionine β-Synthasementioning

confidence: 96%

Defects in homocysteine metabolism: diversity among hyperhomocyst(e)inemias

Matthews

Elmore

2007

Clinical Chemical Laboratory Medicine

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“…Plasma Hcy was measured by HPLC fractionation coupled to fluorescence detection [29]. Plasma Met was measured by HPLC with coulometric electrochemical detection as previously described [27].…”

Section: Plasma Metabolite Measurementsmentioning

confidence: 99%

“…While methionine synthase deficiency is predicted to lead to methyl trapping, or elevated levels of methyltetrahydrofolate in the folate pool, absence of methylenetetrahydrofolate reductase leads to lowered levels of methyltetrahydrofolate [26] and absence of cystathionine-β-synthase is not expected to have any effect on folate pools. Absence of methylenetetrahydrofolate reductase or cystathionine-β-synthase also leads to a decreased intracellular AdoMet/AdoHcy ratio and reduced capacity for biological methylation [26,27]. The present study was initiated to determine whether the phenotype associated with methionine synthase deficiency would be different from that seen in other animal models of hyperhomocyst(e)inemia.…”

Section: Introductionmentioning

confidence: 99%

Metabolic derangement of methionine and folate metabolism in mice deficient in methionine synthase reductase

Elmore

Leclerc

et al. 2007

Molecular Genetics and Metabolism

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122

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Hyperhomocyst(e)inemia is a metabolic derangement that is linked to the distribution of folate pools, which provide one-carbon units for biosynthesis of purines and thymidylate and for remethylation of homocysteine to form methionine. In humans, methionine synthase deficiency results in the accumulation of methyltetrahydrofolate at the expense of folate derivatives required for purine and thymidylate biosynthesis. Complete ablation of methionine synthase activity in mice results in embryonic lethality. Other mouse models for hyperhomocyst(e)inemia have normal or reduced levels of methyltetrahydrofolate and are not embryonic lethal, although they have decreased ratios of AdoMet/AdoHcy and impaired methylation. We have constructed a mouse model with a gene trap insertion in the Mtrr gene specifying methionine synthase reductase, an enzyme essential for the activity of methionine synthase. This model is a hypomorph, with reduced methionine synthase reductase activity, thus avoiding the lethality associated with the absence of methionine synthase activity. Mtrr gt/gt mice have increased plasma homocyst(e)ine, decreased plasma methionine, and increased tissue methyltetrahydrofolate. Unexpectedly, Mtrr gt/gt mice do not show decreases in the AdoMet/AdoHcy ratio in most tissues. The different metabolite profiles in the various genetic mouse models for hyperhomocysteinemia may be useful in understanding biological effects of elevated homocyst(e)ine.

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“…Knockout mouse pathogenesis CBS [137][138][139][140] Hyperhomocysteinemia Hyperkeratosis MAT1A 89 Spontaneous hepatocellular carcinoma and impaired liver regeneration MTHFR 85,141 Hyperhomocysteinemia (À/+ and À/À) Developmental retardation with cerebellar pathology (À/À) Aortic lipid deposition (À/+ and À/À) Abnormal spermatogenesis (À/À) FOLR1 (Folbp1 Embryonic lethality (À/À) mouse homolog) 90 reversed by folinic acid supplementation of (À/+) dams…”

Section: Genementioning

confidence: 99%