华南大学陈临溪研究组的一项最新研究的最新研究揭示了SEC62依赖性ER吞噬参与了apelin-13/APJ诱导的单核细胞-血管内皮细胞粘附在动脉粥样硬化发病机制中的作用。相关论文发表在2025年2月10日出版的《中国药理学报》杂志上。

研究小组之前发现ROS自噬途径参与了血管紧张素结构域1型受体相关蛋白（APJ）及其内源性配体apelin-13诱导的单核细胞-内皮细胞粘附。在本研究中，研究小组研究了apelin-13在这一过程中具体调控了哪种类型的自噬。通过对apelin-13处理的人脐静脉内皮细胞（HUVECs）进行全面转录组学分析，课题组发现ER吞噬受体蛋白SEC62的转录水平显著升高。重要的是，SEC62在人类动脉粥样硬化病变中也上调。因此，课题组研究人员研究了依赖SEC62的ER吞噬对apelin-13诱导的单核细胞内皮细胞粘附和动脉粥样硬化发病机制的影响。

该研究组发现Apelin-13 （0.001 μM）剂量依赖性地上调SEC62的表达，从而诱导HUVECs ER吞噬。这种效应被自噬抑制剂3MA （10 mM）和内质网应激抑制剂salubrinal （10 μM）逆转。siRNA-Sec62、3MA （10 mM）和salubrinal （10 μM）均抑制apelin-13诱导的单核细胞-内皮细胞粘附，而血管内皮细胞特异性SEC62缺失减轻了apelin-13处理的APOE / apelin-13诱导的动脉粥样硬化斑块面积、细胞间粘附分子表达和病变巨噬细胞。高脂肪和高胆固醇饮食的老鼠。

此外，课题组研究人员证明了apelin-13处理的HUVECs中，ALDH1L1的泛素样修饰参与了SEC62依赖性ER吞噬：apelin-13上调小泛素样蛋白UBL4A，介导了ALDH1L1在812-赖氨酸位点的泛素样修饰。这进而促进ALDH1L1插入ER膜，导致SEC62依赖性ER吞噬。研究组发现siRNA-UBL4A、siRNA-ALDH1L1、siRNA-ASNA1和ALDH1L1 812赖氨酸位点突变体均降低了apelin-13诱导的单核细胞内皮细胞粘附。研究团队得出结论，apelin-13诱导SEC62依赖性ER吞噬促进单核细胞内皮细胞粘附和动脉粥样硬化。这项研究揭示了动脉粥样硬化的新机制，并确定了潜在的治疗靶点。

据悉，单核细胞粘附血管内皮细胞是动脉粥样硬化发病的关键步骤。

附：英文原文

Title: SEC62-dependent ER-phagy contributes to apelin-13/APJ-induced monocyte-vascular endothelial cell adhesion in atherosclerosis pathogenesis

Author: Chen, Zhe, Cheng, Jun, Zhou, Qun, Wu, Le-le, Chen, Jia-wei, Duan, Xiang-ning, Yan, Jia-long, Cao, Jian-gang, Xia, Xiao-dan, Li, Lan-fang, Chen, Lin-xi

Issue&Volume: 2025-02-10

Abstract: The monocyte adhesion to vascular endothelial cells constitutes a key step in atherosclerosis pathogenesis. We previously found that ROS-autophagy pathway participated in the monocyte-endothelial cell adhesion induced by angiotensin domain type 1 receptor-associated proteins (APJ) and its endogenous ligand apelin-13. In this study, we investigated what specific type of autophagy apelin-13 regulated in this process. By conducting full-scale transcriptomic analysis in apelin-13-treated human umbilical vein endothelial cells (HUVECs), we found that the transcription levels of ER-phagy receptor protein SEC62 were significantly elevated. Importantly, SEC62 was also upregulated in human atherosclerotic lesions. Thus, we investigated the effects of SEC62-dependent ER-phagy on apelin-13-induced monocyte-endothelial cell adhesion and atherosclerosis pathogenesis. We demonstrated that Apelin-13 (0.0011μM) dose-dependently upregulated SEC62 expression thereby inducing ER-phagy in HUVECs. This effect was reversed by autophagy inhibitor 3MA (10mM) and endoplasmic reticulum stress inhibitor salubrinal (10μM). The siRNA-Sec62, 3MA (10mM), and salubrinal (10μM) all inhibited apelin-13-induced monocyte-endothelial cells adhesion, whereas vascular endothelial cells specific SEC62 deletion alleviated atherosclerotic plaques area, intercellular adhesion molecules expression and lesional macrophages in apelin-13-treated APOE/ mice with high-fat and high-cholesterol diet. Moreover, we demonstrated that ubiquitin-like modification of ALDH1L1 was involved in SEC62-dependent ER-phagy in apelin-13-treated HUVECs: apelin-13 upregulated small ubiquitin-like protein UBL4A, which mediated the ubiquitination-like modification of ALDH1L1 at 812-lysine site. This, in turn, promoted insertion of ALDH1L1 into ER membrane and led to SEC62-dependent ER-phagy. We showed that siRNA-UBL4A, siRNA-ALDH1L1, siRNA-ASNA1, and the mutant of 812 lysine site of ALDH1L1 all decreased apelin-13-induced monocyte-endothelial cell adhesion. We conclude that apelin-13 induces SEC62-dependent ER-phagy to promote monocyte-endothelial cell adhesion and atherosclerosis. This study reveals new mechanisms underlying atherosclerosis and identifies a potential therapeutic target.

DOI: 10.1038/s41401-024-01471-w

Source: https://www.nature.com/articles/s41401-024-01471-w