删除干扰素刺激基因会加重生理衰老小鼠的心脏功能障碍

IF 5.3 3区 医学 Q2 CELL BIOLOGY Mechanisms of Ageing and Development Pub Date : 2024-09-02 DOI:10.1016/j.mad.2024.111978
Diansa Gao , Boying Zhao , Jiang Yu , Xiaorong Li , Ding Yang , Yuan Luo , Yong Xia , Xiongwei Cai , Yongzheng Guo
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引用次数: 0

摘要

背景:干扰素基因刺激器(STING)对先天性免疫反应至关重要。研究表明,cGAS-STING 通路是衰老相关炎症的驱动因素。然而,STING 是否参与了生理衰老过程中的心脏功能障碍仍不清楚:方法:从基因表达总库(Gene Expression Omnibus)数据库中获取基因表达谱,然后进行加权基因共表达网络分析、基因本体分析和蛋白质网络交互分析,以确定与衰老相关的关键通路和基因。用STING基因敲除小鼠研究了STING对生理衰老过程中心脏功能、糖稳态、炎症和自噬的影响:结果:生物信息学分析表明,STING 是一个值得关注的枢纽基因。随后的实验证明,STING通路在衰老小鼠的心脏中被激活。敲除 STING 可减轻老龄小鼠的炎症反应。然而,敲除 STING 会损害糖耐量、抑制自噬、增强氧化应激并加重老年小鼠的心脏功能障碍:结论:通过基因消融长期抑制 STING 虽然能减轻炎症,但会加重老年小鼠的心功能障碍。鉴于衰老的多面性和 STING 除免疫调节外的多种细胞功能,应充分考虑以 STING 为靶点作为缓解衰老表型的策略的负面影响。
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Deletion of stimulator of interferons genes aggravated cardiac dysfunction in physiological aged mice

Background

Stimulator of interferons genes (STING) is crucial for innate immune response. It has been demonstrated that cGAS-STING pathway was the driver of aging-related inflammation. However, whether STING is involved in cardiac dysfunction during the physiological aging process remains unclear.

Methods

Gene expression profiles were obtained from the Gene Expression Omnibus database, followed by weighted gene co-expression network analysis, gene ontology analysis and protein network interaction analysis to identify key pathway and genes associated with aging. The effects of STING on cardiac function, glucose homeostasis, inflammation, and autophagy in physiological aging were investigated with STING knockout mice.

Results

Bioinformatics analysis revealed STING emerged as a hub gene of interest. Subsequent experiments demonstrated the activation of STING pathway in the heart of aged mice. Knockout of STING alleviated the inflammation in aged mice. However, Knockout of STING impaired glucose tolerance, inhibited autophagy, enhanced oxidative stress and aggravated cardiac dysfunction in aged mice.

Conclusion

Although reducing inflammation, long-term STING inhibition by genetic ablation exacerbated cardiac dysfunction in aged mice. Given the multifaceted nature of aging and the diverse cellular functions of STING beyond immune regulation, the negative effects of targeting STING as a strategy to mitigate aging phenotype should be fully considered.

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来源期刊
CiteScore
11.10
自引率
1.90%
发文量
79
审稿时长
32 days
期刊介绍: Mechanisms of Ageing and Development is a multidisciplinary journal aimed at revealing the molecular, biochemical and biological mechanisms that underlie the processes of aging and development in various species as well as of age-associated diseases. Emphasis is placed on investigations that delineate the contribution of macromolecular damage and cytotoxicity, genetic programs, epigenetics and genetic instability, mitochondrial function, alterations of metabolism and innovative anti-aging approaches. For all of the mentioned studies it is necessary to address the underlying mechanisms. Mechanisms of Ageing and Development publishes original research, review and mini-review articles. The journal also publishes Special Issues that focus on emerging research areas. Special issues may include all types of articles following peered review. Proposals should be sent directly to the Editor-in-Chief.
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