Major Vault Protein Prevents Atherosclerotic Plaque Destabilization by Suppressing Macrophage ASK1-JNK Signaling

Qingling Liu, Junlu Pan, Linrui Bao, Chunxiang Xu, Yu Qi, Bin Jiang, Dongdong Wang, Xudong Zhu, Xiaoyu Li, Hanwen Zhang, Hui Bai, Qing Yang, Junqing Ma, Erik A.C. Wiemer, Jingjing Ben, Qi Chen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

6 Citations (Scopus)

Abstract

Background: Macrophages are implicated in atherosclerotic plaque instability by inflammation and degradation of extracellular matrix. However, the regulatory mechanisms driving these macrophage-associated processes are not well understood. Here, we aimed to identify the plaque destabilization-associated cytokines and signaling pathways in macrophages. Methods: The atherosclerotic models of myeloid-specific MVP (major vault protein) knockout mice and control mice were generated. Atherosclerotic instability, macrophage inflammatory signaling, and active cytokines released by macrophages were examined in vivo and in vitro by using cellular and molecular biological approaches. Results: MVP deficiency in myeloid cells exacerbated murine plaque instability by increasing production of both MMP (matrix metallopeptidase)-9 and proinflammatory cytokines in artery wall. Mechanistically, expression of MMP-9 was mediated via ASK1 (apoptosis signal-regulating kinase 1)-MKK-4 (mitogen-activated protein kinase kinase 4)-JNK (c-Jun N-terminal kinase) signaling in macrophages. MVP and its α-helical domain could bind with ASK1 and inhibit its dimerization and phosphorylation. A 62 amino acid peptide (MVP-[686-747]) in the α-helical domain of MVP showed a crucial role in preventing macrophage MMP-9 production and plaque instability. Conclusions: MVP may act as an inhibitor for ASK1-JNK signaling-mediated MMP-9 production in macrophages and, thereby, attenuate unstable plaque formation. Our findings suggest that suppression of macrophage ASK1-JNK signaling may be a useful strategy antagonizing atherosclerotic diseases.

Original languageEnglish
Pages (from-to)580-596
Number of pages17
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume42
Issue number5
Early online date7 Apr 2022
DOIs
Publication statusPublished - May 2022

Bibliographical note

Funding Information:
This work was supported by grants from the National Natural Science Foundation of China (81830011 and 82030012 to Dr Chen; 82070457 and 81870371 to Dr Ben; 82100433 to B. Jiang; 82170444 to X. Zhu; and 81670263 to X. Li); the Natural Science Foundation of the Jiangsu Higher Education Institutions of China (18KJA310003 to Dr Ben and 20KJA310007 to X. Zhu); and the Qing Lan Project.

Publisher Copyright:
© 2022 Lippincott Williams and Wilkins. All rights reserved.

Fingerprint

Dive into the research topics of 'Major Vault Protein Prevents Atherosclerotic Plaque Destabilization by Suppressing Macrophage ASK1-JNK Signaling'. Together they form a unique fingerprint.

Cite this