The Many Flavors of Hyperhomocyst(e)inemia: Insights from Transgenic and Inhibitor-Based Mouse Models of Disrupted One-Carbon Metabolism

Elmore, C. Lee; Matthews, Rowena G.

doi:10.1089/ars.2007.1795

Cited by 13 publications

(11 citation statements)

References 78 publications

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“…The plasma total homocysteine concentration was significantly elevated in Mtrr gt/gt ( Figure 3A) when compared with Mtrr + / + (P < 0.01) and Mtrr + /gt (P < 0.05) mice, as previously reported [17]. Mtrr gt/gt mice had more than 2-fold higher homocysteine compared with the other genotype groups.…”

Section: Increased Plasma Homocysteine and Betaine Concentrations In supporting

confidence: 86%

“…Mtrr gt/gt dams have higher frequencies of adverse reproductive outcomes, including heart defects in offspring; the genotype of the offspring may also contribute to some of the complications [19]. Brain function has not been examined in these mice although MTRR is highly expressed in the developing neural tube and in the adult brain [5,17].…”

Section: Introductionmentioning

confidence: 99%

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Mouse model for deficiency of methionine synthase reductase exhibits short-term memory impairment and disturbances in brain choline metabolism

Jadavji

Bahous

Deng

et al. 2014

Biochemical Journal

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Hyperhomocysteinaemia can contribute to cognitive impairment and brain atrophy. MTRR (methionine synthase reductase) activates methionine synthase, which catalyses homocysteine remethylation to methionine. Severe MTRR deficiency results in homocystinuria with cognitive and motor impairments. An MTRR polymorphism may influence homocysteine levels and reproductive outcomes. The goal of the present study was to determine whether mild hyperhomocysteinaemia affects neurological function in a mouse model with Mtrr deficiency. Mtrr+/+, Mtrr+/gt and Mtrrgt/gt mice (3 months old) were assessed for short-term memory, brain volumes and hippocampal morphology. We also measured DNA methylation, apoptosis, neurogenesis, choline metabolites and expression of ChAT (choline acetyltransferase) and AChE (acetylcholinesterase) in the hippocampus. Mtrrgt/gt mice exhibited short-term memory impairment on two tasks. They had global DNA hypomethylation and decreased choline, betaine and acetylcholine levels. Expression of ChAT and AChE was increased and decreased respectively. At 3 weeks of age, they showed increased neurogenesis. In the cerebellum, mutant mice had DNA hypomethylation, decreased choline and increased expression of ChAT. Our work demonstrates that mild hyperhomocysteinaemia is associated with memory impairment. We propose a mechanism whereby a deficiency in methionine synthesis leads to hypomethylation and compensatory disturbances in choline metabolism in the hippocampus. This disturbance affects the levels of acetylcholine, a critical neurotransmitter in learning and memory.

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Section: Increased Plasma Homocysteine and Betaine Concentrations In supporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Mouse model for deficiency of methionine synthase reductase exhibits short-term memory impairment and disturbances in brain choline metabolism

Jadavji

Bahous

Deng

et al. 2014

Biochemical Journal

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“…Even in the absence of dietary modification, all of the currently available genetic models of hyperhomocysteinemia produce significant alterations in folate pools, SAM levels, or other homocysteine-related metabolites. 31 A future challenge, with important clinical implications, will be to design experimental approaches to distinguish between the direct and indirect vascular effects of hyperhomocysteinemia. Such studies may be facilitated by new murine models, such as the human CBS transgenic mouse, 45 that use inducible promoters to conditionally express CBS or other transgenes.…”

Section: Perspectivesmentioning

confidence: 99%

“…28 -30 Murine models of hyperhomocysteinemia are gaining in popularity for vascular studies because of the availability of many transgenic and gene-targeted strains and because of improvements in methods for the analysis of vascular structure and function in mice. [31][32][33] The purpose of this review is to summarize the availability and utilization of murine models of hyperhomocysteinemia for the investigation of vascular function.…”

mentioning

confidence: 99%

Murine Models of Hyperhomocysteinemia and Their Vascular Phenotypes

Dayal

Lentz

2008

ATVB

104

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Hyperhomocysteinemia is an established risk factor for arterial as well as venous thromboembolism. Individuals with severe hyperhomocysteinemia caused by inherited genetic defects in homocysteine metabolism have an extremely high incidence of vascular thrombosis unless they are treated aggressively with homocysteine-lowering therapy. The clinical value of homocysteine-lowering therapy in individuals with moderate hyperhomocysteinemia, which is very common in populations at risk for vascular disease, is more controversial. Considerable progress in our understanding of the molecular mechanisms underlying the association between hyperhomocysteinemia and vascular thrombotic events has been provided by the development of a variety of murine models. Because levels of homocysteine are regulated by both the methionine and folate cycles, hyperhomocysteinemia can be induced in mice through both genetic and dietary manipulations. Mice deficient in the cystathionine β -synthase (CBS) gene have been exploited widely in many studies investigating the vascular pathophysiology of hyperhomocysteinemia. In this article, we review the established murine models, including the CBS-deficient mouse as well as several newer murine models available for the study of hyperhomocysteinemia. We also summarize the major vascular phenotypes observed in these murine models.

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“…1) (1-3). As a central metabolite in the global sulfur and methylation pathways, Met homeostasis is subject to exquisite regulation that tightly controls fluxes of Met-derived metabolites and Met itself (4,5).…”

mentioning

confidence: 99%

Mammals Reduce Methionine-S-sulfoxide with MsrA and Are Unable to Reduce Methionine-R-sulfoxide, and This Function Can Be Restored with a Yeast Reductase

Lee

Gladyshev

2008

Journal of Biological Chemistry

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Methionine is an essential amino acid in mammals at the junction of methylation, protein synthesis, and sulfur pathways. However, this amino acid is highly susceptible to oxidation, resulting in a mixture of methionine-S-sulfoxide and methionine-R-sulfoxide. Whether methionine is quantitatively regenerated from these compounds is unknown. Here we report that SK-Hep1 hepatocytes grew on methionine-S-sulfoxide and consumed this compound by import and methionine-S-sulfoxide reductase (MsrA)-dependent reduction, but methionine-R-sulfoxide reductases were not involved in this process, and methionine-R-sulfoxide could not be used by the cells. However, SKHep1 cells expressing a yeast free methionine-R-sulfoxide reductase proliferated in the presence of either sulfoxide, reduced them, and showed increased resistance to oxidative stress. Only methionine-R-sulfoxide was detected in the plasma of wild type mice, but both sulfoxides were in the plasma of MsrA knock-out mice. These results show that mammals can support methionine metabolism by reduction of methionine-S-sulfoxide, that this process is dependent on MsrA, that mammals are inherently deficient in the reduction of methionine-R-sulfoxide, and that expression of yeast free methionine-R-sulfoxide reductase can fully compensate for this deficiency.Methionine (Met) is an essential amino acid in mammals. Besides its utilization for protein synthesis, Met supports the cellular S-adenosylmethionine-dependent methylation cycle and is used for biosynthesis of cysteine and other compounds ( Fig. 1) (1-3). As a central metabolite in the global sulfur and methylation pathways, Met homeostasis is subject to exquisite regulation that tightly controls fluxes of Met-derived metabolites and Met itself (4, 5).Despite extensive information on Met regulation, one pathway critical to Met availability and homeostasis did not receive sufficient attention to date. Being a sulfur-containing amino acid, Met, along with Cys, is highly susceptible to oxidation by reactive oxygen species (ROS) 2 generated during oxidative stress and normal cellular metabolism. ROS can oxidize both free Met and Met residues in proteins, resulting in a diastereomeric mixture of Met sulfoxides: Met-S-sulfoxide (Met-SO) and Met-R-sulfoxide (Met-RO) (6, 7).To repair Met-SO and Met-RO residues in proteins, cells have evolved two families of enzymes known as Met sulfoxide reductases: MsrA that is specific for Met-SO and MsrB that specifically reduces Met-RO (8). The active sites of proteins in both Msr families are better adapted for binding Met sulfoxide residues than free Met sulfoxides (6). Although both MsrA and MsrB are capable of reducing free Met sulfoxides (9), a contribution of these enzymes to the reduction of these amino acids is not known (10).Mammals have one MsrA and three MsrB isozymes, with selenoprotein MsrB1 localized to cytosol and nucleus, MsrB2 to mitochondria, and MsrB3 to the endoplasmic reticulum (9). A single MsrA is partitioned into various cellular compartments by alternative first exon s...

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The Many Flavors of Hyperhomocyst(e)inemia: Insights from Transgenic and Inhibitor-Based Mouse Models of Disrupted One-Carbon Metabolism

Cited by 13 publications

References 78 publications

Mouse model for deficiency of methionine synthase reductase exhibits short-term memory impairment and disturbances in brain choline metabolism

Mouse model for deficiency of methionine synthase reductase exhibits short-term memory impairment and disturbances in brain choline metabolism

Murine Models of Hyperhomocysteinemia and Their Vascular Phenotypes

Mammals Reduce Methionine-S-sulfoxide with MsrA and Are Unable to Reduce Methionine-R-sulfoxide, and This Function Can Be Restored with a Yeast Reductase

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