AGEs promote atherosclerosis by increasing LDL transcytosis across endothelial cells via RAGE/NF-κB/Caveolin-1 pathway

Molecular Medicine

Research Article

Xiangli Bai¹  Li Wang¹  Yi Song¹  Si Jin¹  Meng Shu¹  Ying Zhao¹  Yajing Lu¹  Yan Zhu¹  Xiong Jia¹  Yan Shu¹  Wenzhuo Cheng¹  Lin Zhu² 

[1] Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, 39 Lake Road, East Lake Ecological Scenic, 430077, Wuhan, Hubei, China;Department of Pediatrics, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China;

关键词: AGEs;    RAGE;    Diabetic atherosclerosis;    Caveolin-1;    LDL transcytosis;   

DOI  :  10.1186/s10020-023-00715-5

 received in 2023-05-04, accepted in 2023-08-14,  发布年份 2023

来源: Springer

【 摘 要 】

ObjectiveTo elucidate the mechanism whereby advanced glycation end products (AGEs) accelerate atherosclerosis (AS) and to explore novel therapeutic strategies for atherosclerotic cardiovascular disease.Methods and resultsThe effect of AGEs on low-density lipoprotein (LDL) transcytosis across endothelial cells (ECs) was assessed using an in vitro model of LDL transcytosis. We observed that AGEs activated the receptor for advanced glycation end products (RAGE) on the surface of ECs and consequently upregulated Caveolin-1, which in turn increased caveolae-mediated LDL transcytosis and accelerated AS progression. Our molecular assessment revealed that AGEs activate the RAGE-NF-κB signaling, which then recruits the NF-κB subunit p65 to the RAGE promoter and consequently enhances RAGE transcription, thereby forming a positive feedback loop between the NF-κB signaling and RAGE expression. Increased NF-κB signaling ultimately upregulated Caveolin-1, promoting LDL transcytosis, and inhibition of RAGE suppressed AGE-induced LDL transcytosis. In ApoE−/− mice on a high-fat diet, atherosclerotic plaque formation was accelerated by AGEs but suppressed by EC-specific knockdown of RAGE.ConclusionAGEs accelerate the development of diabetes-related AS by increasing the LDL transcytosis in ECs through the activation of the RAGE/NF-κB/Caveolin-1 axis, which may be targeted to prevent or treat diabetic macrovascular complications.

【 授权许可】

CC BY   
© The Feinstein Institute for Medical Research 2023

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