AGEs promote atherosclerosis by increasing LDL transcytosis across endothelial cells via RAGE/NF-κB/Caveolin-1 pathway
Objective To elucidate the mechanism whereby advanced glycation end products (AGEs) accelerate atherosclerosis (AS) and to explore novel therapeutic strategies for atherosclerotic cardiovascular disease. Methods and results The 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. Conclusion AGEs 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..
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:29 |
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| Enthalten in: |
Molecular medicine - 29(2023), 1 vom: 21. Aug. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Shu, Meng [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| Themen: |
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| Anmerkungen: |
© The Author(s) 2023 |
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| doi: |
10.1186/s10020-023-00715-5 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Objective To elucidate the mechanism whereby advanced glycation end products (AGEs) accelerate atherosclerosis (AS) and to explore novel therapeutic strategies for atherosclerotic cardiovascular disease. Methods and results The 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. Conclusion AGEs 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. | ||
| 650 | 4 | |a AGEs |7 (dpeaa)DE-He213 | |
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| 650 | 4 | |a Diabetic atherosclerosis |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Caveolin-1 |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a LDL transcytosis |7 (dpeaa)DE-He213 | |
| 700 | 1 | |a Cheng, Wenzhuo |4 aut | |
| 700 | 1 | |a Jia, Xiong |4 aut | |
| 700 | 1 | |a Bai, Xiangli |4 aut | |
| 700 | 1 | |a Zhao, Ying |4 aut | |
| 700 | 1 | |a Lu, Yajing |4 aut | |
| 700 | 1 | |a Zhu, Lin |4 aut | |
| 700 | 1 | |a Zhu, Yan |4 aut | |
| 700 | 1 | |a Wang, Li |4 aut | |
| 700 | 1 | |a Shu, Yan |4 aut | |
| 700 | 1 | |a Song, Yi |4 aut | |
| 700 | 1 | |a Jin, Si |0 (orcid)0000-0003-0727-6715 |4 aut | |
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