Nε-carboxyethyl-lysin influences atherosclerotic plaque stability through ZKSCAN3 acetylation-regulated macrophage autophagy via the RAGE/LKB1/AMPK1/SIRT1 pathway
Abstract Atherosclerosis, a chronic inflammatory condition characterized by plaque formation, often leads to instability, particularly under Type 2 diabetes mellitus (T2DM) conditions, which exacerbate cardiovascular risks. However, the molecular mechanisms underlying this process remain incompletel...
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BMC
2025-01-01
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| Series: | Cardiovascular Diabetology |
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| Online Access: | https://doi.org/10.1186/s12933-025-02586-y |
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| author | Zhongwei Liu Jing Liu Xiqiang Wang Yong Zhang Yanpeng Ma Gongchang Guan Ya Yuwen Ni He Hanxiu Liu Xingfeng Yu Sen Ma Junkui Wang Jin Zhang Ling Zhu Yulian Zhang |
| author_facet | Zhongwei Liu Jing Liu Xiqiang Wang Yong Zhang Yanpeng Ma Gongchang Guan Ya Yuwen Ni He Hanxiu Liu Xingfeng Yu Sen Ma Junkui Wang Jin Zhang Ling Zhu Yulian Zhang |
| author_sort | Zhongwei Liu |
| collection | DOAJ |
| description | Abstract Atherosclerosis, a chronic inflammatory condition characterized by plaque formation, often leads to instability, particularly under Type 2 diabetes mellitus (T2DM) conditions, which exacerbate cardiovascular risks. However, the molecular mechanisms underlying this process remain incompletely understood. In this study, we investigated the correlation between acute coronary syndrome (ACS) and serum levels of Nε-carboxyethyl-lysin (CEL), a prominent advanced glycation end product (AGE) elevated in T2DM, in a cohort of 225 patients with coronary artery disease. Using a murine model of atherosclerosis complicated by T2DM, we examined the effects of CEL on plaque stability and macrophage autophagy. Our findings revealed that elevated serum CEL levels are independently associated with increased ACS incidence. Metabolomic profiling identified CEL as a key AGE contributing to plaque instability in diabetic conditions. Mechanistically, CEL disrupted macrophage autophagy and plaque stability by perturbing the Receptor for Advanced Glycation End products (RAGE)/Liver Kinase B1 (LKB1)/AMP-activated Protein Kinase 1 (AMPK1)/Sirtuin 1 (SIRT1) signaling cascade. This pathway further regulated autophagic activity through SIRT1-mediated acetylation of Zinc Finger with KRAB and SCAN Domains 3 (ZKSCAN3). These findings highlight CEL’s critical role in promoting plaque instability in T2DM by impairing key molecular pathways that regulate autophagy, offering potential therapeutic targets for managing atherosclerosis in diabetic patients. |
| format | Article |
| id | doaj-art-42d55c7072d240379ea879166fdbd9f4 |
| institution | Kabale University |
| issn | 1475-2840 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Cardiovascular Diabetology |
| spelling | doaj-art-42d55c7072d240379ea879166fdbd9f42025-01-26T12:13:40ZengBMCCardiovascular Diabetology1475-28402025-01-0124111710.1186/s12933-025-02586-yNε-carboxyethyl-lysin influences atherosclerotic plaque stability through ZKSCAN3 acetylation-regulated macrophage autophagy via the RAGE/LKB1/AMPK1/SIRT1 pathwayZhongwei Liu0Jing Liu1Xiqiang Wang2Yong Zhang3Yanpeng Ma4Gongchang Guan5Ya Yuwen6Ni He7Hanxiu Liu8Xingfeng Yu9Sen Ma10Junkui Wang11Jin Zhang12Ling Zhu13Yulian Zhang14Department of Cardiology, Shaanxi Provincial People’s HospitalDepartment of Cardiology, Shaanxi Provincial People’s HospitalDepartment of Cardiology, Shaanxi Provincial People’s HospitalDepartment of Cardiology, Shaanxi Provincial People’s HospitalDepartment of Cardiology, Shaanxi Provincial People’s HospitalDepartment of Cardiology, Shaanxi Provincial People’s HospitalDepartment of Cardiology, Shaanxi Provincial People’s HospitalDepartment of Cardiology, Shaanxi Provincial People’s HospitalDepartment of Cardiology, Shaanxi Provincial People’s HospitalDepartment of Nursing, Shaanxi Provincial People’s HospitalDepartment of Technology Transfer and Management, Shaanxi Provincial People’s HospitalDepartment of Cardiology, Shaanxi Provincial People’s HospitalDepartment of Otolaryngology, Shaanxi Provincial People’s HospitalDepartment of Cardiology, Shaanxi Provincial People’s HospitalThe Director’s Office, Shaanxi Provincial People’s HospitalAbstract Atherosclerosis, a chronic inflammatory condition characterized by plaque formation, often leads to instability, particularly under Type 2 diabetes mellitus (T2DM) conditions, which exacerbate cardiovascular risks. However, the molecular mechanisms underlying this process remain incompletely understood. In this study, we investigated the correlation between acute coronary syndrome (ACS) and serum levels of Nε-carboxyethyl-lysin (CEL), a prominent advanced glycation end product (AGE) elevated in T2DM, in a cohort of 225 patients with coronary artery disease. Using a murine model of atherosclerosis complicated by T2DM, we examined the effects of CEL on plaque stability and macrophage autophagy. Our findings revealed that elevated serum CEL levels are independently associated with increased ACS incidence. Metabolomic profiling identified CEL as a key AGE contributing to plaque instability in diabetic conditions. Mechanistically, CEL disrupted macrophage autophagy and plaque stability by perturbing the Receptor for Advanced Glycation End products (RAGE)/Liver Kinase B1 (LKB1)/AMP-activated Protein Kinase 1 (AMPK1)/Sirtuin 1 (SIRT1) signaling cascade. This pathway further regulated autophagic activity through SIRT1-mediated acetylation of Zinc Finger with KRAB and SCAN Domains 3 (ZKSCAN3). These findings highlight CEL’s critical role in promoting plaque instability in T2DM by impairing key molecular pathways that regulate autophagy, offering potential therapeutic targets for managing atherosclerosis in diabetic patients.https://doi.org/10.1186/s12933-025-02586-yAdvanced glycation end productsNε-carboxyethyl-lysinAtherosclerotic plaque vulnerabilityMacrophage autophagyType 2 diabetes mellitus |
| spellingShingle | Zhongwei Liu Jing Liu Xiqiang Wang Yong Zhang Yanpeng Ma Gongchang Guan Ya Yuwen Ni He Hanxiu Liu Xingfeng Yu Sen Ma Junkui Wang Jin Zhang Ling Zhu Yulian Zhang Nε-carboxyethyl-lysin influences atherosclerotic plaque stability through ZKSCAN3 acetylation-regulated macrophage autophagy via the RAGE/LKB1/AMPK1/SIRT1 pathway Cardiovascular Diabetology Advanced glycation end products Nε-carboxyethyl-lysin Atherosclerotic plaque vulnerability Macrophage autophagy Type 2 diabetes mellitus |
| title | Nε-carboxyethyl-lysin influences atherosclerotic plaque stability through ZKSCAN3 acetylation-regulated macrophage autophagy via the RAGE/LKB1/AMPK1/SIRT1 pathway |
| title_full | Nε-carboxyethyl-lysin influences atherosclerotic plaque stability through ZKSCAN3 acetylation-regulated macrophage autophagy via the RAGE/LKB1/AMPK1/SIRT1 pathway |
| title_fullStr | Nε-carboxyethyl-lysin influences atherosclerotic plaque stability through ZKSCAN3 acetylation-regulated macrophage autophagy via the RAGE/LKB1/AMPK1/SIRT1 pathway |
| title_full_unstemmed | Nε-carboxyethyl-lysin influences atherosclerotic plaque stability through ZKSCAN3 acetylation-regulated macrophage autophagy via the RAGE/LKB1/AMPK1/SIRT1 pathway |
| title_short | Nε-carboxyethyl-lysin influences atherosclerotic plaque stability through ZKSCAN3 acetylation-regulated macrophage autophagy via the RAGE/LKB1/AMPK1/SIRT1 pathway |
| title_sort | nε carboxyethyl lysin influences atherosclerotic plaque stability through zkscan3 acetylation regulated macrophage autophagy via the rage lkb1 ampk1 sirt1 pathway |
| topic | Advanced glycation end products Nε-carboxyethyl-lysin Atherosclerotic plaque vulnerability Macrophage autophagy Type 2 diabetes mellitus |
| url | https://doi.org/10.1186/s12933-025-02586-y |
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