mPEG@ELA-11 Alleviates Atherosclerosis via AKT-ER Stress-Mediated Macrophage Modulation

  • BME Front. 2025 Nov 25:6:0203. doi: 10.34133/bmef.0203.
Xiaoguang Li  1  2 ,  Ning Dou  1 ,  Linshan Zhong  3 ,  Yicheng Wu  2 ,  ZhenZhen Cai  4 ,  Zaixu Zhao  5 ,  Lefeng Qu  2 ,  Qixia Jiang  6
Affiliations
  • 1. Center of Vascular Diseases, Shanghai Fourth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai 200434, China.
  • 2. Department of Vascular and Endovascular Surgery, Changzheng Hospital Affiliated to the Naval Medical University, Shanghai 200003, China.
  • 3. Department of Cardiovascular Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China.
  • 4. Department of Clinical Laboratory, Shanghai Fourth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai 200434, China.
  • 5. Department of Biological Medicines and Shanghai Engineering Research Center of Immunotherapeutics, School of Pharmacy, Fudan University, Shanghai, China.
  • 6. Department of Cardiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
PMID: 41306397 DOI: 10.34133/bmef.0203
Abstract

Objective: This study explores the role of methoxy polyethylene glycol@Elabela-11 (mPEG@ELA-11), a pH-responsive ELA-11 conjugate, in modulating macrophage function and attenuating atherosclerosis, focusing on the protein kinase B (Akt)-mediated endoplasmic reticulum (ER) stress pathway as a molecular target. Impact Statement: We reveal that ELA-11 alleviates atherosclerosis by suppressing macrophage foam cell formation, M1 polarization, and Apoptosis via the AKT-ER stress pathway. We also develop mPEG@ELA-11, a novel pH-responsive nanocarrier, to enhance targeted drug delivery and therapeutic efficacy, offering a breakthrough for peptide-based cardiovascular nanomedicine. Introduction: Atherosclerosis, driven by macrophage dysfunction and lipid accumulation, is a major global killer. ELA-11, a fragment of Elabela peptide, shows cardiovascular protective effects, but its role in atherosclerosis and optimal delivery remain unstudied. Methods: Elabela mRNA (APELA) expression was analyzed in human carotid atherosclerotic plaques using real-time quantitative PCR analysis, and serum ELA levels were quantified via enzyme-linked immunosorbent assay in patients with carotid stenosis. In vitro studies on RAW264.7 macrophages evaluated mPEG@ELA-11 effects on oxidized low-density lipoprotein-induced foam cell formation, polarization, and Apoptosis. In vivo efficacy was tested in apoE-/- mice, comparing mPEG@ELA-11 with free ELA-11, and its pH-responsive release mechanism was characterized. Results: APELA was down-regulated in human atherosclerotic plaques, especially unstable lesions. mPEG@ELA-11 suppressed foam cell formation, M1 polarization, and Apoptosis by inhibiting the AKT-ER stress pathway in vitro. In mice, it reduced plaque area more effectively than free ELA-11 attributed to pH-triggered release. Conclusion: The pH-responsive mPEG@ELA-11 alleviates atherosclerosis by modulating macrophages via the AKT-ER stress pathway, with favorable targeting and safety, representing a promising targeted peptide nanomedicine for atherosclerosis.

Products