Analysis of MTHFR, CBS, glutathione, taurine, and hydrogen sulfide levels in retinas of hyperhomocysteinemic mice

Xuezhi Cui, Soumya Navneet, Jing Wang, Penny Roon, Wei Chen, Ming Xian, Sylvia B Smith

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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 b-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 (H2S), 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-b-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 H2 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 H2S 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 H2S are maintained at robust levels. Elevation of H2S is particularly intriguing owing to neuroprotective properties reported for this gasotransmitter.

Original languageEnglish (US)
Pages (from-to)1954-1963
Number of pages10
JournalInvestigative Ophthalmology and Visual Science
Volume58
Issue number4
DOIs
StatePublished - Apr 1 2017

Fingerprint

Glutathione Synthase
Cystathionine
Methylenetetrahydrofolate Reductase (NADPH2)
Hydrogen Sulfide
Taurine
Retina
Hyperhomocysteinemia
Ganglia
Glutathione
Gasotransmitters
Mutant Strains Mice
Cystathionine gamma-Lyase
RNA
Retinal Diseases
Glutathione Disulfide
Cysteine
Proteins
Phenotype
Mutation

Keywords

  • Ganglion cell
  • Homocysteine
  • One carbon metabolism
  • Remethylation pathway
  • Retina
  • Transsulfuration pathway

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

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.

In: Investigative Ophthalmology and Visual Science, Vol. 58, No. 4, 01.04.2017, p. 1954-1963.

Research output: Contribution to journalArticle

@article{9b691f8ea79741abb7d04227c3caedd2,
title = "Analysis of MTHFR, CBS, glutathione, taurine, and hydrogen sulfide levels in retinas of hyperhomocysteinemic mice",
abstract = "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 b-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 (H2S), 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-b-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 H2 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 H2S 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 H2S are maintained at robust levels. Elevation of H2S is particularly intriguing owing to neuroprotective properties reported for this gasotransmitter.",
keywords = "Ganglion cell, Homocysteine, One carbon metabolism, Remethylation pathway, Retina, Transsulfuration pathway",
author = "Xuezhi Cui and Soumya Navneet and Jing Wang and Penny Roon and Wei Chen and Ming Xian and Smith, {Sylvia B}",
year = "2017",
month = "4",
day = "1",
doi = "10.1167/iovs.16-21247",
language = "English (US)",
volume = "58",
pages = "1954--1963",
journal = "Investigative Ophthalmology and Visual Science",
issn = "0146-0404",
publisher = "Association for Research in Vision and Ophthalmology Inc.",
number = "4",

}

TY - JOUR

T1 - Analysis of MTHFR, CBS, glutathione, taurine, and hydrogen sulfide levels in retinas of hyperhomocysteinemic mice

AU - Cui, Xuezhi

AU - Navneet, Soumya

AU - Wang, Jing

AU - Roon, Penny

AU - Chen, Wei

AU - Xian, Ming

AU - Smith, Sylvia B

PY - 2017/4/1

Y1 - 2017/4/1

N2 - 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 b-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 (H2S), 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-b-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 H2 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 H2S 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 H2S are maintained at robust levels. Elevation of H2S is particularly intriguing owing to neuroprotective properties reported for this gasotransmitter.

AB - 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 b-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 (H2S), 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-b-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 H2 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 H2S 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 H2S are maintained at robust levels. Elevation of H2S is particularly intriguing owing to neuroprotective properties reported for this gasotransmitter.

KW - Ganglion cell

KW - Homocysteine

KW - One carbon metabolism

KW - Remethylation pathway

KW - Retina

KW - Transsulfuration pathway

UR - http://www.scopus.com/inward/record.url?scp=85017206164&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85017206164&partnerID=8YFLogxK

U2 - 10.1167/iovs.16-21247

DO - 10.1167/iovs.16-21247

M3 - Article

C2 - 28384716

AN - SCOPUS:85017206164

VL - 58

SP - 1954

EP - 1963

JO - Investigative Ophthalmology and Visual Science

JF - Investigative Ophthalmology and Visual Science

SN - 0146-0404

IS - 4

ER -