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

Acta Pharmacologica Sinica volume 46, pages 1652–1663 (2025)Cite this article

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 (0.001−1 μM) dose-dependently upregulated SEC62 expression thereby inducing ER-phagy in HUVECs. This effect was reversed by autophagy inhibitor 3MA (10 mM) and endoplasmic reticulum stress inhibitor salubrinal (10 μM). The siRNA-Sec62, 3MA (10 mM), and salubrinal (10 μM) 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.

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Fig. 1: Apelin-13/APJ induced SEC62-dependent ER-phagy in HUVECs.
Fig. 2: SEC62-dependent ER-phagy was involved in Apelin-13-stimulated monocyte-vascular endothelial cell adhesion and atherosclerotic development.
Fig. 3: Ubiquitin-like modification of ALDH1L1 contributed Apelin-13/APJ to promote SEC62-dependent ER-phagy.
Fig. 4: UBL4A upregulated by Apelin-13 mediate the ubiquitination-like modification ALDH1L1.
Fig. 5: Ubiquitination-like modification of ALDH1L1 via UBL4A mediated apelin-13-stimulated monocyte-vascular endothelial cell adhesion.
Fig. 6: Ubiquitin-like modification of ALDH1L1 at 812 K caused SEC62-dependent ER-phagy to mediate monocyte-vascular endothelial cell adhesion and atherosclerosis induced by Apelin-13/APJ.

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Acknowledgements

This work was supported by the grants from the National Natural Science Foundation of China (Grant number: 81603108), Natural Science Foundation of Hunan Province (Grant number: 2023JJ30555), Natural Science Foundation of Guangdong Province (Guangdong Natural Science Foundation, 2023A1515010295) and Health Research Project of Hunan Provincial Health Commission (202103011014).

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  1. These authors contributed equally: Zhe Chen, Jun Cheng, Qun Zhou, Le-le Wu

Authors and Affiliations

  1. Institute of Pharmacy and Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, College of Basic Medical Science, Hengyang Medical School, University of South China, Hengyang, China

    Zhe Chen, Le-le Wu, Jia-wei Chen, Xiang-ning Duan, Jia-long Yan, Lan-fang Li & Lin-xi Chen

  2. Changde Hospital, Xiangya School of Medicine, Central South University (The First People’s Hospital of Changde City), Changde, China

    Jun Cheng

  3. Hunan Province Key Laboratory for Antibody-based Drug and Intelligent Delivery System, School of Pharmaceutical Sciences, Hunan University of Medicine, Huaihua, China

    Qun Zhou

  4. The Affiliated Nanhua Hospital, Clinical Pharmacy Research Institute, Hengyang Medical School, University of South China, Hengyang, China

    Jian-gang Cao

  5. Department of Orthopedics, Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan People’s Hospital, Qingyuan, China

    Xiao-dan Xia

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Contributions

LXC and LFL designed research, administered, and supervised the project. ZC, JC, and JLY the experimental parts of the research. XND and JWC generated and characterized the mouse models. QZ and LLW analyzed data. ZC and JGC wrote the paper. LXC and XDX checked the content and language of manuscript. All authors commented on and approved the manuscript for submission.

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Correspondence to Jian-gang Cao, Xiao-dan Xia, Lan-fang Li or Lin-xi Chen.

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Chen, Z., Cheng, J., Zhou, Q. et al. SEC62-dependent ER-phagy contributes to apelin-13/APJ-induced monocyte-vascular endothelial cell adhesion in atherosclerosis pathogenesis. Acta Pharmacol Sin 46, 1652–1663 (2025). https://doi.org/10.1038/s41401-024-01471-w

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