Objective:This study explores the role of methoxy polyethylene glycol@Elabela-11(mPEG@ELA-11),a pHresponsive ELA-11 conjugate,in modulating macrophage function and attenuating atherosclerosis,focusing on the protein k...Objective:This study explores the role of methoxy polyethylene glycol@Elabela-11(mPEG@ELA-11),a pHresponsive 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 downregulated 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.展开更多
基金supported by the National Natural Science Foundation of China(82270481,82470481,and 82370498)the Shuang Bai Ren Project of Shanghai Jiao Tong University(JYYJXYS20240821)the Medical Scientific Research Project of Shanghai Hongkou Health Commission(Hongwei 2302-17 and 2302-22).
文摘Objective:This study explores the role of methoxy polyethylene glycol@Elabela-11(mPEG@ELA-11),a pHresponsive 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 downregulated 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.
