June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Delineating the Role of Soluble Epoxide Hydrolase in the Aging Retina
Author Affiliations & Notes
  • Caroline Manicam
    Department of Ophthalmology, Universitatsmedizin der Johannes Gutenberg-Universitat Mainz, Mainz, Rheinland-Pfalz, Germany
  • Elahe Zare
    Department of Ophthalmology, Universitatsmedizin der Johannes Gutenberg-Universitat Mainz, Mainz, Rheinland-Pfalz, Germany
  • Mario Dejung
    Institute of Molecular Biology (IMB), Mainz, Germany
  • Falk Butter
    Institute of Molecular Biology (IMB), Mainz, Germany
  • Franz Grus
    Department of Ophthalmology, Universitatsmedizin der Johannes Gutenberg-Universitat Mainz, Mainz, Rheinland-Pfalz, Germany
  • Norbert Pfeiffer
    Department of Ophthalmology, Universitatsmedizin der Johannes Gutenberg-Universitat Mainz, Mainz, Rheinland-Pfalz, Germany
  • Natarajan Perumal
    Department of Ophthalmology, Universitatsmedizin der Johannes Gutenberg-Universitat Mainz, Mainz, Rheinland-Pfalz, Germany
  • Footnotes
    Commercial Relationships   Caroline Manicam None; Elahe Zare None; Mario Dejung None; Falk Butter None; Franz Grus None; Norbert Pfeiffer None; Natarajan Perumal None
  • Footnotes
    Support  German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) grant MA 8006/1-1
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 60. doi:
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      Caroline Manicam, Elahe Zare, Mario Dejung, Falk Butter, Franz Grus, Norbert Pfeiffer, Natarajan Perumal; Delineating the Role of Soluble Epoxide Hydrolase in the Aging Retina. Invest. Ophthalmol. Vis. Sci. 2023;64(8):60.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Aging is a main risk factor for retinal degeneration in glaucoma. The cytochrome P450 (CYP) lipid metabolic pathway plays a pivotal role in retinal neurovascular functions. Vasoactive CYP metabolites are degraded by soluble epoxide hydrolase (sEH), thereby diminishing their beneficial effects. Hence, sEH inhibitors have emerged as novel treatment agents. This study tested the hypothesis that the inhibition of sEH confers neuro-vasculoprotective effects in the aging retina.

Methods : Young male mice (3-5 months) and old mice (12-24 months) with null Ephx2 gene (KO) and wild type controls (WT) were used in this study. Retinae were isolated from 80 mice and pooled (n=5 mice/group/replicate) to yield 4 biological replicates per group. Samples were subjected to robust mass spectrometry (MS)-based proteomics and in-silico bioinformatics analyses.

Results : A total of 3706 retinal proteins were identified. The sEH KO resulted in significant (p<0.05) differential expressions of 175 proteins. Aging had a profound effect on the retina as demonstrated by the differential expressions of 183 and 155 proteins in the WT and KO mice, respectively. Noteworthy, sEH KO had a major influence on the regulation of proteins involved in the activation of oxidative phosphorylation (OXPHOS, p=1.32E-06) and inhibition of mitochondrial dysfunction (p=3.39E-03), which corresponded to upstream involvement of UQCC3 (p=7.29E-07) required for bioenergetic reprogramming via mitochondrial homeostasis. The key molecular mechanistic changes attributed to aging were implicated in the inhibition of the NAD+ (p=9.08E-04) and sirtuin (p=6.18E-03) signalling pathways-both of which are associated with age-related cellular dysfunction and DNA damage. Remarkably, retina of aged KO mice resulted in significant changes in the proteins involved in the regulation of eIF2 signalling (p=1.15E-12), and the two downstream signals of mTOR comprising eIF4 and p70S6K (p=6.15E-05). A translation regulator, LARP1, which regulates cell proliferation primarily via the regulation of protein synthesis was highly significantly activated in the aged KO retina (p=9.97E-16) compared to aged WT retina (p= 3.10E-05).

Conclusions : We provide the first in-depth experimental data that support our hypothesis that the lack of sEH significantly ameliorates age-related detrimental changes in the retina. The potential adjunct use of sEH inhibitors for glaucoma therapy needs further investigation.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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