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Invest Ophthalmol Vis Sci. 2017 Apr 1;58(4):1954-1963. doi: 10.1167/iovs.16-21247.

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

Author information

1
Department of Cellular Biology and Anatomy, The Medical College of Georgia at Augusta University, Augusta, Georgia, United States 2The James and Jean Culver Vision Discovery Institute, Augusta University, Augusta, Georgia, United States.
2
Department of Cellular Biology and Anatomy, The Medical College of Georgia at Augusta University, Augusta, Georgia, United States.
3
Department of Chemistry, Washington State University, Pullman, Washington, United States.
4
Department of Cellular Biology and Anatomy, The Medical College of Georgia at Augusta University, Augusta, Georgia, United States 2The James and Jean Culver Vision Discovery Institute, Augusta University, Augusta, Georgia, United States 4Department of Ophthalmology, Augusta University, Augusta, Georgia, United States.

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 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 (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-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 H2S.

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.

PMID:
28384716
PMCID:
PMC5381329
DOI:
10.1167/iovs.16-21247
[Indexed for MEDLINE]
Free PMC Article

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