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Deficiency of LAMP2A in macrophages accelerates hypoxia-induced atherosclerosis by inhibiting BNIP3-mediated

Ning Wang1, Zhiyuan Wang1, Pinpeng Xie1

  • 1National Key Laboratory for Innovation and Transformation of Luobing Theory; the Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences; Department of Cardiology, Qilu Hospital of Shandong University, Jinan, Shandong, China.

International Immunopharmacology
|May 20, 2026
PubMed

Insights

Deficiency in chaperone-mediated autophagy (CMA) accelerates hypoxia-induced atherosclerosis by impairing mitophagy. Upregulating BNIP3 can restore mitophagy in LAMP2A-deficient macrophages, offering potential therapeutic targets for atherosclerosis.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Cardiovascular Research

Background:

  • Chaperone-mediated autophagy (CMA) degrades proteins in lysosomes and its impairment accelerates atherosclerosis under normoxia.
  • Hypoxia is a risk factor for atherosclerosis, but CMA's role under hypoxic conditions remains unclear.
  • LAMP2A is the rate-limiting component of CMA.

Purpose of the Study:

  • To investigate the role of CMA in hypoxia-induced atherosclerosis.
  • To elucidate the underlying molecular mechanisms involving LAMP2A, mitophagy, and BNIP3.

Main Methods:

  • Generated myeloid-specific LAMP2A-knockout mice and LAMP2A-deficient THP-1 macrophage cells.
  • Exposed ApoE-/- mice to hypoxic conditions to study atherosclerosis development.
  • Analyzed LAMP2A expression in patient PBMCs and mouse atherosclerotic plaques.
  • Investigated the impact of LAMP2A deficiency on mitophagy and BNIP3 expression.
  • Utilized miR-134-5p and BNIP3 manipulation to explore mechanistic pathways.

Main Results:

  • LAMP2A expression increased in PBMCs from obstructive sleep apnoea syndrome patients and in hypoxic atherosclerotic plaques.
  • LAMP2A knockout in macrophages exacerbated hypoxia-induced atherosclerosis and impaired mitophagy.
  • LAMP2A deficiency inhibited BNIP3 expression via miR-134-5p, leading to mitophagy impairment.
  • Restoring BNIP3 expression rescued mitophagy function in LAMP2A-deficient macrophages.

Conclusions:

  • Macrophage LAMP2A deficiency accelerates hypoxia-induced atherosclerosis.
  • This acceleration is partly mediated by the inhibition of BNIP3-dependent mitophagy via miR-134-5p.
  • Targeting the LAMP2A-miR-134-5p-BNIP3 axis may offer therapeutic strategies for hypoxia-related atherosclerosis.
Keywords:
AtherosclerosisBNIP3Chaperone-mediated autophagyHypoxiaMitophagy

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