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Analysis of MTHFR, CBS, Glutathione, Taurine, and Hydrogen Sulfide Levels in Retinas of Hyperhomocysteinemic Mice

PURPOSE: Hyperhomocysteinemia (Hhcy) is implicated in certain retinal neurovascular diseases, although whether it is causative remains uncertain. In isolated ganglion cells (GCs), mild Hhcy induces profound death, whereas retinal phenotypes in Hhcy mice caused by mutations in remethylation (methylen...

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Autores principales: Cui, Xuezhi, Navneet, Soumya, Wang, Jing, Roon, Penny, Chen, Wei, Xian, Ming, Smith, Sylvia B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Association for Research in Vision and Ophthalmology 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5381329/
https://www.ncbi.nlm.nih.gov/pubmed/28384716
http://dx.doi.org/10.1167/iovs.16-21247
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author Cui, Xuezhi
Navneet, Soumya
Wang, Jing
Roon, Penny
Chen, Wei
Xian, Ming
Smith, Sylvia B.
author_facet Cui, Xuezhi
Navneet, Soumya
Wang, Jing
Roon, Penny
Chen, Wei
Xian, Ming
Smith, Sylvia B.
author_sort Cui, Xuezhi
collection PubMed
description PURPOSE: Hyperhomocysteinemia (Hhcy) is implicated in certain retinal neurovascular diseases, although whether it is causative remains uncertain. In isolated ganglion cells (GCs), mild Hhcy induces profound death, whereas retinal phenotypes in Hhcy mice caused by mutations in remethylation (methylene tetrahydrofolatereductase [Mthfr(+/−)]) or transsulfuration pathways (cystathionine β-synthase [Cbs(+/−)]) demonstrate mild GC loss and mild vasculopathy. The current work investigated compensation in vivo of one pathway for the other, and, because the transsulfuration pathway yields cysteine necessary for formation of glutathione (GSH), taurine, and hydrogen sulfide (H(2)S), they were analyzed also. METHODS: Retinas isolated from wild-type (WT), Mthfr(+/−), and Cbs(+/−) mice (12 and 22 weeks) were analyzed for methylene tetrahydrofolate reductase (MTHFR), cystathionine-β-synthase (CBS), and cystathionase (CTH) RNA/protein levels. Retinas were evaluated for levels of reduced:oxidized GSH (GSH:GSSG), Slc7a11 (xCT), taurine, taurine transporter (TAUT), and H(2)S. RESULTS: Aside from decreased CBS RNA/protein levels in Cbs(+/−) retinas, there were minimal alterations in remethylation/transsulfuration pathways in the two mutant mice strains. Glutathione and taurine levels in Mthfr(+/−) and Cbs(+/−) retinas were similar to WT, which may be due to robust levels of xCT and TAUT in mutant retinas. Interestingly, levels of H(2)S were markedly increased in retinas of Mthfr(+/−) and Cbs(+/−) mice compared with WT. CONCLUSIONS: Ganglion cell loss and vasculopathy observed in Mthfr(+/−) and Cbs(+/−) mouse retinas may be milder than expected, not because of compensatory increases of enzymes in remethylation/transsulfuration pathways, but because downstream transsulfuration pathway products GSH, taurine, and H(2)S are maintained at robust levels. Elevation of H(2)S is particularly intriguing owing to neuroprotective properties reported for this gasotransmitter.
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spelling pubmed-53813292017-04-07 Analysis of MTHFR, CBS, Glutathione, Taurine, and Hydrogen Sulfide Levels in Retinas of Hyperhomocysteinemic Mice Cui, Xuezhi Navneet, Soumya Wang, Jing Roon, Penny Chen, Wei Xian, Ming Smith, Sylvia B. Invest Ophthalmol Vis Sci Retinal Cell Biology PURPOSE: Hyperhomocysteinemia (Hhcy) is implicated in certain retinal neurovascular diseases, although whether it is causative remains uncertain. In isolated ganglion cells (GCs), mild Hhcy induces profound death, whereas retinal phenotypes in Hhcy mice caused by mutations in remethylation (methylene tetrahydrofolatereductase [Mthfr(+/−)]) or transsulfuration pathways (cystathionine β-synthase [Cbs(+/−)]) demonstrate mild GC loss and mild vasculopathy. The current work investigated compensation in vivo of one pathway for the other, and, because the transsulfuration pathway yields cysteine necessary for formation of glutathione (GSH), taurine, and hydrogen sulfide (H(2)S), they were analyzed also. METHODS: Retinas isolated from wild-type (WT), Mthfr(+/−), and Cbs(+/−) mice (12 and 22 weeks) were analyzed for methylene tetrahydrofolate reductase (MTHFR), cystathionine-β-synthase (CBS), and cystathionase (CTH) RNA/protein levels. Retinas were evaluated for levels of reduced:oxidized GSH (GSH:GSSG), Slc7a11 (xCT), taurine, taurine transporter (TAUT), and H(2)S. RESULTS: Aside from decreased CBS RNA/protein levels in Cbs(+/−) retinas, there were minimal alterations in remethylation/transsulfuration pathways in the two mutant mice strains. Glutathione and taurine levels in Mthfr(+/−) and Cbs(+/−) retinas were similar to WT, which may be due to robust levels of xCT and TAUT in mutant retinas. Interestingly, levels of H(2)S were markedly increased in retinas of Mthfr(+/−) and Cbs(+/−) mice compared with WT. CONCLUSIONS: Ganglion cell loss and vasculopathy observed in Mthfr(+/−) and Cbs(+/−) mouse retinas may be milder than expected, not because of compensatory increases of enzymes in remethylation/transsulfuration pathways, but because downstream transsulfuration pathway products GSH, taurine, and H(2)S are maintained at robust levels. Elevation of H(2)S is particularly intriguing owing to neuroprotective properties reported for this gasotransmitter. The Association for Research in Vision and Ophthalmology 2017-04 /pmc/articles/PMC5381329/ /pubmed/28384716 http://dx.doi.org/10.1167/iovs.16-21247 Text en Copyright 2017 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
spellingShingle Retinal Cell Biology
Cui, Xuezhi
Navneet, Soumya
Wang, Jing
Roon, Penny
Chen, Wei
Xian, Ming
Smith, Sylvia B.
Analysis of MTHFR, CBS, Glutathione, Taurine, and Hydrogen Sulfide Levels in Retinas of Hyperhomocysteinemic Mice
title Analysis of MTHFR, CBS, Glutathione, Taurine, and Hydrogen Sulfide Levels in Retinas of Hyperhomocysteinemic Mice
title_full Analysis of MTHFR, CBS, Glutathione, Taurine, and Hydrogen Sulfide Levels in Retinas of Hyperhomocysteinemic Mice
title_fullStr Analysis of MTHFR, CBS, Glutathione, Taurine, and Hydrogen Sulfide Levels in Retinas of Hyperhomocysteinemic Mice
title_full_unstemmed Analysis of MTHFR, CBS, Glutathione, Taurine, and Hydrogen Sulfide Levels in Retinas of Hyperhomocysteinemic Mice
title_short Analysis of MTHFR, CBS, Glutathione, Taurine, and Hydrogen Sulfide Levels in Retinas of Hyperhomocysteinemic Mice
title_sort analysis of mthfr, cbs, glutathione, taurine, and hydrogen sulfide levels in retinas of hyperhomocysteinemic mice
topic Retinal Cell Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5381329/
https://www.ncbi.nlm.nih.gov/pubmed/28384716
http://dx.doi.org/10.1167/iovs.16-21247
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