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

IF 3 3区医学 Q1 OPHTHALMOLOGY

Acta Ophthalmologica Pub Date : 2025-01-19 DOI:10.1111/aos.17097

Caroline Manicam, Elahe Zare, Norbert Pfeiffer, Natarajan Perumal

{"title":"Molecular responses of the aging retina are sexually divergent in Ephx2−/− mice","authors":"Caroline Manicam, Elahe Zare, Norbert Pfeiffer, Natarajan Perumal","doi":"10.1111/aos.17097","DOIUrl":null,"url":null,"abstract":"<div>\n \n <section>\n \n 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.\n \n 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.\n \n 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).\n \n 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.\n </section>\n </div>","PeriodicalId":6915,"journal":{"name":"Acta Ophthalmologica","volume":"103 S284","pages":""},"PeriodicalIF":3.0000,"publicationDate":"2025-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/10.1111/aos.17097","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Acta Ophthalmologica","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/aos.17097","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"OPHTHALMOLOGY","Score":null,"Total":0}

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.

查看原文本刊更多论文

在Ephx2−/−小鼠中，老化视网膜的分子反应存在性别差异

目的/目的：异常分子变化是年龄相关性视网膜病变的主要驱动因素。此外，两性二态性是疾病偏好的一个关键变量，尽管它在临床前研究中没有很好地定义。在减轻视力障碍引起的年龄相关蛋白质组修饰的潜在靶点中，我们最近揭示了可溶性环氧化物水解酶（sEH/ Ephx2）抑制对青光眼的保护作用。在这里，我们假设在Ephx2-/- (KO)小鼠中，老化视网膜的分子反应也存在性别差异。方法：从160只雌雄幼龄（3-5月龄）和老年（12-24月龄）野生型（WT）和KO小鼠中分离视网膜。样本被合并（n = 5只小鼠/组/重复），每组4个生物重复，并进行强大的蛋白质组学和生物信息学分析，以阐明潜在的机制变化。结果：我们观察到雌雄小鼠的年龄和性别相关的体重变化，WT和KO小鼠之间无显著差异。蛋白质组分析显示，不同性别之间的蛋白质表达存在显著差异（p < 0.05），在两性中，eIF2和铁下垂信号通路都有显著参与。值得注意的是，雌性对铁下垂表现出惊人的恢复力，而雄性在这两个WT中都表现出这一途径的深度激活(p = 4.2×10-4；z-score: 1.3)和KO小鼠(p = 4.2×10-4；有趣的是，老年WT女性对视网膜疾病（p = 9.6×10-4）和神经变性（p = 9.9×10-4）非常敏感，但KO显著调节与突触发生（p = 3.8×10-2）和神经传递（p = 1.7×10-2）相关的蛋白质。此外，KO在两性中显著激活了神经新生（p = 5.4×10-5）和细胞间接触（p = 1.2×10-3）。值得注意的是，一个主要的上游转录调节因子，X-box结合蛋白1 (XBP1)，通过改善内质网应激来维持蛋白质稳态，只在老年男性视网膜中被发现(WT: p = 3.9×10-4；KO: p = 8.1×10-3)。综上所述，我们首次发现了衰老KO视网膜蛋白质组的性别相关趋势，这对于理解年龄相关视网膜疾病的病理机制基础和潜在的靶向干预至关重要。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

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.