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

doi:10.1167/iovs.16-21247

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

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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 and Sylvia B Smith

Investigative ophthalmology & visual science, Vol.58(4), pp.1954-1963

04/01/2017

DOI: https://doi.org/10.1167/iovs.16-21247

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https://hdl.handle.net/2376/113695

PMCID: PMC5381329

PMID: 28384716

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Abstract

Hydrogen Sulfide - metabolism

Retinal Diseases - genetics

Retina - metabolism

Glutathione - metabolism

Mice, Inbred C57BL

Gene Expression Regulation

Hyperhomocysteinemia - metabolism

Retinal Diseases - metabolism

Retinal Ganglion Cells - metabolism

Methylenetetrahydrofolate Reductase (NADPH2) - biosynthesis

RNA - genetics

Retinal Ganglion Cells - pathology

Animals

Methylenetetrahydrofolate Reductase (NADPH2) - genetics

Mice, Mutant Strains

Retinal Diseases - etiology

Hyperhomocysteinemia - genetics

Mice

Hyperhomocysteinemia - complications

Real-Time Polymerase Chain Reaction

Retina - pathology

Taurine - metabolism

Disease Models, Animal

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. 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. 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. 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.

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Title: Analysis of MTHFR, CBS, Glutathione, Taurine, and Hydrogen Sulfide Levels in Retinas of Hyperhomocysteinemic Mice
Creators: Xuezhi Cui - 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
Soumya Navneet - 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
Jing Wang - 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
Penny Roon - Department of Cellular Biology and Anatomy, The Medical College of Georgia at Augusta University, Augusta, Georgia, United States
Wei Chen - Department of Chemistry, Washington State University, Pullman, Washington, United States
Ming Xian - Department of Chemistry, Washington State University, Pullman, Washington, United States
Sylvia B Smith - 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
Publication Details: Investigative ophthalmology & visual science, Vol.58(4), pp.1954-1963
Academic Unit: Chemistry, Department of
Publisher: United States
Grant note: R01 HL116571 / NHLBI NIH HHS R01 EY012830 / NEI NIH HHS
Identifiers: 99900548288201842
Language: English
Resource Type: Journal article