Xu Yitong, Chen Jingxuan, Liu Yiran, Zhang Ge, Miao Guolin, Wu Jingdong, Lu Kaikai, Zhao Yinqi, Zhang Wenxi, Zheng Liwen, Zhang Lianxin, Chen Jinxuan, Zhou Zihao, Han Yufei, Lai Pingping, Guo Jiabao, Wu Donghui, Mei Si, Zhang Ling, Zhao Yang, Huang Wei, Wang Yuhui, Tang Junnan, Zhao Dongyu, Xian Xunde
Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences, Peking University, No. 38 Xueyuan Road, Haidian District, Beijing 100191, People's Republic of China.
Department of Biomedical Informatics, School of Basic Medical Sciences, Peking University, No. 38 Xueyuan Road, Haidian District, Beijing 100191, People´s of Republic of China.
Eur Heart J. 2025 Jul 25. doi: 10.1093/eurheartj/ehaf523.
Atherosclerosis is a chronic inflammatory disorder with high morbidity and mortality rates worldwide. Emerging evidence has reported that kinesin family member 13B (KIF13B), a crucial motor protein, integrates hepatic lipid metabolism and inflammatory response to protect liver disease. However, the relationship between KIF13B and atherosclerosis remains unknown. The present study aimed to elucidate the specific role of KIF13B in atherosclerosis and its potential therapeutic significance.
The investigation first assessed the relationship between the expression levels of KIF13B and the progression of atherosclerosis in human cohort data and carotid plaques from patients. Subsequently, the authors generated Kif13b knockout (Kif13b-/-) mice on low-density lipoprotein receptor (Ldlr)-deficient background (Ldlr-/-) to obtain double knockouts (Kif13b-/-;Ldlr-/-) and myeloid-specific Kif13b knockout mice (Lyz2 Cre;Kif13bf/f) with adeno-associated virus 8 (AAV8)-mediated overexpression of proprotein convertase subtilisin/kexin type 9 (PCSK9). Moreover, Ldlr-/- mice received bone marrow transplants from either Kif13b-/-;Ldlr-/- or Ldlr-/- mice and were fed a Western diet (WD) for 12 weeks.
KIF13B expression was significantly reduced in patients with atherosclerosis and negatively associated with the severity of atherosclerotic progress in WD-fed Ldlr-/- mice. In contrast to Kif13b-/-;Ldlr-/- mice showing a significant increase in plasma total cholesterol and more atherosclerosis lesions compared with the corresponding control mice, depletion of myeloid-derived Kif13b and bone marrow transplantation with macrophages lacking Kif13b both did not alter plasma lipid levels but elicited the larger atherosclerotic plaques with increased macrophage infiltration and more apoptotic cells. In vitro studies showed that upon oxidized low-density lipoprotein treatment, macrophages with Kif13b deficiency also display significantly increased cholesterol accumulation and impaired efferocytosis with reduced MER proto-oncogene, tyrosine kinase (MERTK) expression. Mechanistic study revealed that loss of Kif13b decreased the expression of Itchy E3 ubiquitin protein ligase (ITCH), leading to accelerated ubiquitination and degradation of MERTK mediated by Casitas B-lineage lymphoma (CBL) in macrophages. Moreover, oral administration of NX-1607, a CBL antagonist, significantly reversed the reduction of MERTK protein level and defective efferocytosis, ultimately protecting against atherosclerotic development caused by Kif13b deficiency in vivo.
The study results revealed that KIF13B is a crucial modulator responsible for maintaining proper macrophage efferocytosis to prevent atherosclerotic development through KIF13B/ITCH/CBL/MERTK axis, suggesting that KIF13B will be a potential therapeutic target for the treatment of atherosclerosis in future clinical trials.
动脉粥样硬化是一种慢性炎症性疾病，在全球范围内发病率和死亡率都很高。新出现的证据表明，驱动蛋白家族成员13B（KIF13B）作为一种关键的运动蛋白，整合肝脏脂质代谢和炎症反应以保护肝脏疾病。然而，KIF13B与动脉粥样硬化之间的关系仍不清楚。本研究旨在阐明KIF13B在动脉粥样硬化中的具体作用及其潜在的治疗意义。
该研究首先在人类队列数据和患者的颈动脉斑块中评估KIF13B表达水平与动脉粥样硬化进展之间的关系。随后，作者在低密度脂蛋白受体（Ldlr）缺陷背景（Ldlr-/-）下生成Kif13b基因敲除（Kif13b-/-）小鼠，以获得双敲除小鼠（Kif13b-/-;Ldlr-/-），以及通过腺相关病毒8（AAV8）介导的前蛋白转化酶枯草溶菌素/kexin 9型（PCSK9）过表达构建的髓系特异性Kif13b基因敲除小鼠（Lyz2 Cre;Kif13bf/f）。此外，给Ldlr-/-小鼠移植来自Kif13b-/-;Ldlr-/-或Ldlr-/-小鼠的骨髓，并给予西方饮食（WD）喂养12周。
在动脉粥样硬化患者中，KIF13B表达显著降低，并且在喂食WD的Ldlr-/-小鼠中，其与动脉粥样硬化进展的严重程度呈负相关。与相应的对照小鼠相比，Kif13b-/-;Ldlr-/-小鼠的血浆总胆固醇显著增加，动脉粥样硬化病变更多；而髓系来源的Kif13b缺失以及用缺乏Kif13b的巨噬细胞进行骨髓移植，均未改变血浆脂质水平，但引发了更大的动脉粥样硬化斑块，伴有巨噬细胞浸润增加和更多凋亡细胞。体外研究表明，在氧化低密度脂蛋白处理后，缺乏Kif13b的巨噬细胞也表现出胆固醇积累显著增加，以及吞噬功能受损，同时原癌基因酪氨酸激酶（MERTK）表达降低。机制研究表明，Kif13b缺失会降低瘙痒E3泛素蛋白连接酶（ITCH）的表达，导致巨噬细胞中由Casitas B系淋巴瘤（CBL）介导的MERTK加速泛素化和降解。此外，口服CBL拮抗剂NX-1607可显著逆转MERTK蛋白水平的降低和吞噬功能缺陷，最终在体内预防由Kif13b缺失引起的动脉粥样硬化发展。
研究结果表明，KIF13B是一种关键调节因子，通过KIF13B/ITCH/CBL/MERTK轴维持适当的巨噬细胞吞噬功能，从而预防动脉粥样硬化发展，这表明KIF13B将成为未来临床试验中治疗动脉粥样硬化的潜在治疗靶点。
