Macrophage-derived KIF13B interacts with USP9X to attenuate abdominal aortic aneurysm development by potentiating TFEB stability.

IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Theranostics Pub Date : 2025-08-16 eCollection Date: 2025-01-01 DOI:10.7150/thno.118958
Jingxuan Chen, Yitong Xu, Huahui Yu, Yiran Liu, Guolin Miao, Yufei Han, Liwen Zheng, Zeyu Cai, Zihao Zhou, Jinxuan Chen, Sijing Shi, Pingping Lai, Wenxi Zhang, Lianxin Zhang, Si Mei, Yinqi Zhao, Ling Zhang, Wei Huang, Yuhui Wang, Dongyu Zhao, Wei Kong, Yanwen Qin, Erdan Dong, Xunde Xian
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引用次数: 0

Abstract

Rationale: Abdominal aortic aneurysm (AAA) is a highly lethal cardiovascular disorder for which there is no effective medication to date. Kinesin family member 13b (KIF13B), a vital motor protein, has been recently identified as a novel regulator of lipid metabolism. However, the role of KIF13B in AAA development has not been documented. Methods: We determined the expression of KIF13B in aortic tissues from clinical patients and porcine pancreatic elastase (PPE) or angiotensin II (ANG II)-induced AAA mouse models. To investigate the influence of KIF13B on AAA expansion, we established global, myeloid cell-specific and vascular smooth muscle cell (VSMC)-specific conditional Kif13b-deficient mice in PPE and/or ANG II-induced AAA models. Results: RNA-seq data from GEO database (GSE57691) revealed a significant decrease in KIF13B gene expression within the aortic tissues of patients with AAA. KIF13B protein levels were largely reduced in aortic tissue samples from patients and two mouse models with AAA. Complete inactivation of Kif13b or depleting Kif13b from myeloid cells but not smooth muscle cells (SMCs) exacerbated AAA development. Mechanistic studies identified transcription factor EB (TFEB) as a critical downstream target of KIF13B. KIF13B stabilized and upregulated TFEB by enhancing its deubiquitination through an interaction with deubiquitinase USP9X to maintain the proper function of lysosomes, thus inhibiting the senescence-associated secretory phenotype (SASP) and proinflammatory response of macrophages. Moreover, restoration of macrophage Kif13b or senolytic therapy dramatically mitigated AAA expansion in vivo. Conclusions: In the present study, we provided a new insight into the pathogenesis of AAA and defined a KIF13B-USP9X-TFEB axis that is essential for the regulation of macrophage function, suggesting that macrophage-derived Kif13b is a beneficial regulator of vascular homeostasis and targeting KIF13B could be a potential therapeutic approach for the treatment of human AAA disease in future clinical trial.

巨噬细胞来源的KIF13B与USP9X相互作用,通过增强TFEB稳定性来减弱腹主动脉瘤的发展。
理由:腹主动脉瘤(AAA)是一种高度致命的心血管疾病,迄今为止尚无有效的药物治疗。运动蛋白家族成员13b (KIF13B)是一种重要的运动蛋白,最近被发现是一种新的脂质代谢调节因子。然而,KIF13B在AAA发展中的作用尚未有文献记载。方法:我们检测了KIF13B在临床患者和猪胰腺弹性蛋白酶(PPE)或血管紧张素II (ANG II)诱导的AAA小鼠主动脉组织中的表达。为了研究KIF13B对AAA扩展的影响,我们在PPE和/或ANG ii诱导的AAA模型中建立了全局、髓细胞特异性和血管平滑肌细胞(VSMC)特异性条件KIF13B缺陷小鼠。结果:GEO数据库(GSE57691)的RNA-seq数据显示,AAA患者主动脉组织中KIF13B基因表达显著降低。来自AAA患者和两种小鼠模型的主动脉组织样本中KIF13B蛋白水平大幅降低。KIF13B完全失活或髓细胞而非平滑肌细胞(SMCs)中KIF13B的消耗加剧了AAA的发展。机制研究发现转录因子EB (TFEB)是KIF13B的关键下游靶点。KIF13B通过与去泛素酶USP9X相互作用,增强TFEB的去泛素化,从而稳定和上调TFEB,维持溶酶体的正常功能,从而抑制巨噬细胞的衰老相关分泌表型(senescence associated secretory phenotype, SASP)和促炎反应。此外,巨噬细胞Kif13b修复或抗衰老治疗可显著减轻体内AAA扩张。结论:在本研究中,我们对AAA的发病机制提供了新的认识,并确定了巨噬细胞功能调节所必需的Kif13b - usp9x - tfeb轴,提示巨噬细胞来源的Kif13b是血管稳态的有益调节因子,靶向Kif13b可能是未来临床试验中治疗人类AAA病的潜在治疗方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Theranostics
Theranostics MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
25.40
自引率
1.60%
发文量
433
审稿时长
1 months
期刊介绍: Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.
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