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Updated: Sep 27, 2025

A Human Ex Vivo Atherosclerotic Plaque Model to Study Lesion Biology
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Major Vault Protein Prevents Atherosclerotic Plaque Destabilization by Suppressing Macrophage ASK1-JNK Signaling

Qingling Liu1, Junlu Pan1, Linrui Bao1

  • 1Department of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, China (Q.L., J.P., L.B., C.X., Y.Q., B.J., D.W., X.Z., X.L., H.Z., H.B., Q.Y., J.M., J.B., Q.C.).

Arteriosclerosis, Thrombosis, and Vascular Biology
|April 7, 2022
PubMed
Abstract

Insights

Major vault protein (MVP) deficiency worsens atherosclerotic plaque instability by increasing MMP-9. MVP inhibits ASK1-JNK signaling, suggesting this pathway as a therapeutic target for atherosclerosis.

Area of Science:

  • Cardiovascular Biology
  • Immunology
  • Molecular Medicine

Background:

  • Macrophages contribute to atherosclerotic plaque instability through inflammation and extracellular matrix degradation.
  • Regulatory mechanisms of macrophage-driven plaque destabilization remain poorly understood.
  • This study aimed to identify key cytokines and signaling pathways in macrophages associated with plaque destabilization.

Purpose of the Study:

  • To investigate the role of major vault protein (MVP) in regulating macrophage function during atherosclerosis.
  • To elucidate the signaling pathways involved in MVP-mediated control of plaque instability.
  • To identify potential therapeutic targets for preventing atherosclerotic plaque rupture.

Main Methods:

  • Generated myeloid-specific MVP knockout mice and control littermates for atherosclerosis studies.
  • Assessed atherosclerotic plaque instability, macrophage inflammatory signaling, and cytokine production in vivo and in vitro.
  • Utilized cellular and molecular biology techniques to examine protein interactions and signaling pathways.

Main Results:

  • MVP deficiency in myeloid cells exacerbated murine plaque instability, increasing matrix metallopeptidase-9 (MMP-9) and pro-inflammatory cytokine production.
  • MVP deficiency led to increased apoptosis signal-regulating kinase 1 (ASK1)-JNK signaling pathway activation in macrophages.
  • MVP directly binds to ASK1, inhibiting its dimerization and phosphorylation, thereby suppressing MMP-9 expression.

Conclusions:

  • MVP acts as a negative regulator of ASK1-JNK signaling, controlling macrophage-derived MMP-9 production and attenuating unstable plaque formation.
  • Targeting the ASK1-JNK signaling pathway in macrophages presents a potential therapeutic strategy for antagonizing atherosclerotic disease progression.
  • MVP's α-helical domain is crucial for inhibiting macrophage MMP-9 production and maintaining plaque stability.
Keywords:
apoptosis signal-regulating kinase 1atherosclerosiscytokinesinflammationmacrophagesmatrix metalloproteinase 9

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