Xiang Xuying, Qin Mengting, Nie Lei, Guo Xiaoqing, Chen Jiaojiao, Jiang Dailiang, Zhang Zhentao, Mao Ling
Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (X.X., M.Q., L.N., X.G., J.C., D.J., L.M.).
Department of Neurology, Renmin Hospital of Wuhan University, China (Z.Z.).
Arterioscler Thromb Vasc Biol. 2025 Aug;45(8):e355-e373. doi: 10.1161/ATVBAHA.125.322536. Epub 2025 Jun 26.
The migration of vascular smooth muscle cells (VSMCs) is critical for the development of atherosclerosis. However, the underlying molecular mechanisms are not completely understood. Here, we detected FAM49B (family with sequence similarity 49 member B) fragments in atherosclerotic plaques and identified their roles in VSMC migration and atherogenesis.
Transgenic mice such as (asparagine endopeptidase), , and VSMC-specific full-length FAM49B and FAM49B fragment overexpression by adenovirus gene transfer were used to determine the role of FAM49B fragments in atherosclerosis. In addition, the effects of compound 11, an AEP inhibitor, on the progression of atherosclerosis in mice were analyzed. FAM49B fragments were identified by mass spectrometry. Moreover, the expression of FAM49B fragments in atherosclerotic plaques from mice and patients was analyzed by immunofluorescence and immunoblotting.
The levels of FAM49B are increased in atherosclerotic lesions. Interestingly, FAM49B is cleaved by the cysteine protease AEP at residues N169 and N170, generating 2 fragments: FAM49B (1-169) and FAM49B (171-324). Both fragments are upregulated in VSMCs with the development of atherosclerotic plaques. The overexpression of full-length FAM49B inhibits the migration of human aortic VSMCs, whereas the overexpression of FAM49B fragments promotes VSMC migration. FAM49B fragments bind to Rac1 (Ras-related C3 botulinum toxin substrate 1) and increase its activity, thereby inducing actin polymerization and promoting cell migration. The overexpression of FAM49B fragments in mouse aortic VSMCs results in a higher atherosclerotic plaque burden, whereas the deletion of AEP blocks FAM49B fragmentation and decreases plaque size in mouse models of atherosclerosis. Furthermore, the administration of compound 11 blocked FAM49B fragmentation and alleviated atherosclerotic lesions.
Our results indicate that AEP-derived FAM49B fragments facilitate Rac1-mediated VSMC migration and promote atherosclerosis progression. Inhibiting AEP-mediated FAM49B fragmentation may be a therapeutic strategy for atherosclerosis.
血管平滑肌细胞（VSMC）的迁移对动脉粥样硬化的发展至关重要。然而，其潜在的分子机制尚未完全阐明。在此，我们检测了动脉粥样硬化斑块中的FAM49B（序列相似性家族49成员B）片段，并确定了它们在VSMC迁移和动脉粥样硬化发生中的作用。
使用诸如天冬酰胺内肽酶（AEP）、[此处可能有遗漏信息]、[此处可能有遗漏信息]等转基因小鼠，以及通过腺病毒基因转移实现VSMC特异性全长FAM49B和FAM49B片段过表达，以确定FAM49B片段在动脉粥样硬化中的作用。此外，分析了AEP抑制剂化合物11对[此处可能有遗漏信息]小鼠动脉粥样硬化进展的影响。通过质谱鉴定FAM49B片段。此外，通过免疫荧光和免疫印迹分析FAM49B片段在小鼠和患者动脉粥样硬化斑块中的表达。
FAM49B在动脉粥样硬化病变中的水平升高。有趣的是，FAM49B在N169和N170残基处被半胱氨酸蛋白酶AEP切割，产生2个片段：FAM49B（1 - 169）和FAM49B（171 - 324）。随着动脉粥样硬化斑块的发展，这两个片段在VSMC中均上调。全长FAM49B的过表达抑制人主动脉VSMC的迁移，而FAM49B片段的过表达促进VSMC迁移。FAM49B片段与Rac1（Ras相关的C3肉毒杆菌毒素底物1）结合并增加其活性，从而诱导肌动蛋白聚合并促进细胞迁移。FAM49B片段在小鼠主动脉VSMC中的过表达导致更高的动脉粥样硬化斑块负担，而在动脉粥样硬化小鼠模型中删除AEP可阻断FAM49B片段化并减小斑块大小。此外，给予化合物11可阻断FAM49B片段化并减轻动脉粥样硬化病变。
我们的结果表明，AEP衍生的FAM49B片段促进Rac1介导的VSMC迁移并促进动脉粥样硬化进展。抑制AEP介导的FAM49B片段化可能是动脉粥样硬化的一种治疗策略。
