Wu Senyan, Tan Xiaoni, Cheng Guobing
Department of Vascular Surgery, Quzhou People's Hospital, The Quzhou Affiliated Hospital of Wenzhou Medical University, 100 Minjiang Avenue, Kecheng District, Quzhou, 324000, Zhejiang, China.
Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Wuhan, 430081, Hubei, China.
Eur J Med Res. 2025 Aug 21;30(1):781. doi: 10.1186/s40001-025-02994-6.
Endothelial cell apoptosis and oxidative stress are pivotal drivers of atherosclerosis (AS) progression. It was revealed that spectrin beta, non-erythrocytic 1 (SPTBN1) levels were remarkably decreased in the atherosclerotic plaque vessels of advanced lesions. This study aimed to elucidate the roles of SPTBN1 in endothelial dysfunction during AS progression.
SPTBN1 levels in the plasma samples of AS patients and aortic tissues of AS mouse model were tested. Human umbilical vein endothelial cells (HUVECs) were stimulated with oxidized low-density lipoprotein (ox-LDL) to mimic atherosclerotic conditions. After transfection of SPTBN1 overexpression plasmids, cell viability, apoptosis, oxidative stress marker including reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD), and inflammatory molecules including vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) were examined. Then, the interaction of SPTBN1 and methyltransferase-like 14 (METTL14) was examined using co-immunoprecipitation assay. The m6A methylation level of tripartite motif-containing 37 (TRIM37) was determined using methylated RNA immunoprecipitation-qPCR (MeRIP-qPCR). Additionally, the effects of SPTBN1 overexpression on atherosclerotic plaque formation were assessed in a high-fat diet-induced AS mouse model.
SPTBN1 was downregulated in plasma samples of AS patients andaortic tissues of AS mouse model. SPTBN1 overexpression suppressed apoptosis, oxidative stress, and inflammation in ox-LDL-treated HUVECs. Mechanistically, SPTBN1 inhibited TRIM37 expression by promoting METTL14-mediated TRIM37 m6A methylation. TRIM37 overexpression abolished the protective effects of SPTBN1 on ox-LDL-treated HUVECs. TRIM37 promoted K63-linked ubiquitination of tumor necrosis factor receptor-associated factor 2 (TRAF2) and activated the NF-κB pathway in HUVECs. Furthermore, SPTBN1 overexpression alleviated atherosclerotic plaque formation, arterial lesions and inflammation in AS mice.
SPTBN1 overexpression suppressed apoptosis, oxidative stress, and inflammation in ox-LDL-treated HUVECs by regulating the TRIM37/TRAF2/NF-κB pathway, thereby inhibiting AS development in mice. Our findings advance understanding of the molecular basis of endothelial homeostasis and identify a potential therapeutic target for AS.
内皮细胞凋亡和氧化应激是动脉粥样硬化（AS）进展的关键驱动因素。研究发现，在晚期病变的动脉粥样硬化斑块血管中，非红细胞β-血影蛋白1（SPTBN1）水平显著降低。本研究旨在阐明SPTBN1在AS进展过程中对内皮功能障碍的作用。
检测AS患者血浆样本和AS小鼠模型主动脉组织中的SPTBN1水平。用氧化型低密度脂蛋白（ox-LDL）刺激人脐静脉内皮细胞（HUVECs）以模拟动脉粥样硬化状态。转染SPTBN1过表达质粒后，检测细胞活力、凋亡、氧化应激标志物（包括活性氧（ROS）、丙二醛（MDA）和超氧化物歧化酶（SOD））以及炎症分子（包括血管细胞黏附分子-1（VCAM-1）和细胞间黏附分子-1（ICAM-1））。然后，使用免疫共沉淀法检测SPTBN1与甲基转移酶样14（METTL14）的相互作用。使用甲基化RNA免疫沉淀定量PCR（MeRIP-qPCR）测定含三联基序蛋白37（TRIM37）的m6A甲基化水平。此外，在高脂饮食诱导的AS小鼠模型中评估SPTBN1过表达对动脉粥样硬化斑块形成的影响。
AS患者血浆样本和AS小鼠模型主动脉组织中的SPTBN1表达下调。SPTBN1过表达抑制了ox-LDL处理的HUVECs中的细胞凋亡、氧化应激和炎症。机制上，SPTBN1通过促进METTL14介导的TRIM37 m6A甲基化来抑制TRIM37表达。TRIM37过表达消除了SPTBN1对ox-LDL处理的HUVECs的保护作用。TRIM37促进肿瘤坏死因子受体相关因子2（TRAF2）的K63连接泛素化并激活HUVECs中的NF-κB通路。此外，SPTBN1过表达减轻了AS小鼠的动脉粥样硬化斑块形成、动脉病变和炎症。
SPTBN1过表达通过调节TRIM37/TRAF2/NF-κB通路抑制ox-LDL处理的HUVECs中的细胞凋亡、氧化应激和炎症，从而抑制小鼠AS的发展。我们的研究结果促进了对内皮稳态分子基础的理解，并确定了AS的潜在治疗靶点。
