Molecular responses of the aging retina are sexually divergent in Ephx2−/− mice

IF 3 3区 医学 Q1 OPHTHALMOLOGY
Caroline Manicam, Elahe Zare, Norbert Pfeiffer, Natarajan Perumal
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引用次数: 0

Abstract

Aims/Purpose: Aberrant molecular changes are a major driver of age-related retinopathies. Furthermore, sexual dimorphism is a key variable in disease predilection, although it is not well defined in preclinical studies. Among the potential targets for mitigating age-related proteome modifications attributed to vision impairment, we recently unraveled the protective effects of soluble epoxide hydrolase (sEH/ Ephx2) inhibition in glaucoma. Here, we hypothesized that molecular responses of the aging retina are also sexually divergent in the Ephx2-/- (KO) mice.

Methods: Retinae were isolated from 160 young (3-5 months) and old (12-24 months) wild type (WT) and KO mice of both sexes. Samples were pooled (n = 5 mice/group/replicate) with 4 biological replicates per group and subjected to robust proteomic and bioinformatic analyses to elucidate the underlying mechanistic changes.

Results: We observed age- and sex-related body weight changes in mice of both sexes, with no significant differences between the WT and KO mice. Proteome profiling showed significant (p < 0.05) differential expression of proteins between the genders, with a significant involvement in the eIF2 and ferroptosis signaling pathways in both sexes. Remarkably, the female sex exhibited striking resilience against ferroptosis, while the male counterpart demonstrated profound activation of this pathway in both WT (p = 4.2×10-4; z-score: 1.3) and KO mice (p = 4.2×10-4; z-score: 2). Intriguingly, aged WT females were highly susceptible to retinal diseases (p = 9.6×10-4) and neurodegeneration (p = 9.9×10-4), but KO significantly regulated proteins related to synaptogenesis (p = 3.8×10-2) and neurotransmission (p = 1.7×10-2). In addition, KO significantly activated neuritogenesis (p = 5.4×10-5) and cell-cell contact (p = 1.2×10-3) in both sexes. It is noteworthy that a major upstream transcription regulator, X-box binding protein 1 (XBP1), which is responsible for maintaining protein homeostasis by ameliorating ER stress, was found only in aged male retinae (WT: p = 3.9×10-4; KO: p = 8.1×10-3).

Conclusions: Taken together, we showed for the first time a sex-related trend in the proteome of aging KO retina, which is crucial for understanding the pathomechanistic underpinnings of age-related retinal diseases and potential targeted intervention.

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来源期刊
Acta Ophthalmologica
Acta Ophthalmologica 医学-眼科学
CiteScore
7.60
自引率
5.90%
发文量
433
审稿时长
6 months
期刊介绍: Acta Ophthalmologica is published on behalf of the Acta Ophthalmologica Scandinavica Foundation and is the official scientific publication of the following societies: The Danish Ophthalmological Society, The Finnish Ophthalmological Society, The Icelandic Ophthalmological Society, The Norwegian Ophthalmological Society and The Swedish Ophthalmological Society, and also the European Association for Vision and Eye Research (EVER). Acta Ophthalmologica publishes clinical and experimental original articles, reviews, editorials, educational photo essays (Diagnosis and Therapy in Ophthalmology), case reports and case series, letters to the editor and doctoral theses.
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