Disturbed shear stress promotes atherosclerosis through TRIM21‐regulated MAPK6 degradation and consequent endothelial inflammation
Abstract Rationale Coronary artery plaques often develop in regions subjected to disturbed shear stress (DSS), yet the mechanisms underlying this phenomenon remain poorly understood. Our study aimed to elucidate the unknown role of MAPK6 in shear stress and plaque formation. Methods In vitro and in...
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Wiley
2025-01-01
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| Series: | Clinical and Translational Medicine |
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| Online Access: | https://doi.org/10.1002/ctm2.70168 |
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| author | Feng Wang Shu‐Yu Wang Yue Gu Shuai Luo Ai‐Qun Chen Chao‐Hua Kong Wen‐Ying Zhou Li‐Guo Wang Zhi‐Mei Wang Guang‐Feng Zuo Xiao‐Fei Gao Jun‐Jie Zhang Shao‐Liang Chen |
| author_facet | Feng Wang Shu‐Yu Wang Yue Gu Shuai Luo Ai‐Qun Chen Chao‐Hua Kong Wen‐Ying Zhou Li‐Guo Wang Zhi‐Mei Wang Guang‐Feng Zuo Xiao‐Fei Gao Jun‐Jie Zhang Shao‐Liang Chen |
| author_sort | Feng Wang |
| collection | DOAJ |
| description | Abstract Rationale Coronary artery plaques often develop in regions subjected to disturbed shear stress (DSS), yet the mechanisms underlying this phenomenon remain poorly understood. Our study aimed to elucidate the unknown role of MAPK6 in shear stress and plaque formation. Methods In vitro and in vivo experiments, RNA‐seq, CO‐IP and proteomic analysis, combined with single‐cell RNA‐seq datasets were used to reveal the upstream and downstream mechanisms involved. AAV‐MAPK6, ApoE−/−MAPK6flox/floxTEKCre mice and the CXCL12 neutraligand were used to confirm the beneficial effects of MAPK6 against atherosclerosis. Results Our study revealed a substantial decrease in MAPK6 protein levels in endothelial cells in response to DSS, both in vivo and in vitro, which was contingent on the binding of the ubiquitin ligase TRIM21 to MAPK6. Endothelium‐specific MAPK6 overexpression exerts antiatherosclerotic effects in ApoE−/− mice, elucidating the unexplored role of MAPK6 in atherosclerosis. Comprehensive RNA‐seq, integrated single‐cell mapping and further experiments unveiled the involvement of MAPK6 in inflammation through the EGR1/CXCL12 axis. ApoE−/−MAPK6flox/floxTEKCre mice finally confirmed that conditional MAPK6 knockout resulted in endothelial inflammation and significant increases in plaque areas. Notably, these effects could be reversed through the neutralization of CXCL12. Conclusions Our study illuminates the advantages of MAPK6 in decelerating plaque progression, highlighting the potential of safeguarding MAPK6 as a novel therapeutic strategy against atherosclerosis. Key points Disturbed flow activates the ubiquitin‒proteasome degradation pathway of MAPK6 in endothelial cells, which is contingent on the binding of the ubiquitin ligase TRIM21 to MAPK6. Endothelial MAPK6 has an advantageous impact on decelerating plaque progression. MAPK6 regulates endothelial inflammation via the EGR1/CXCL12 axis. |
| format | Article |
| id | doaj-art-7363500a87c6480dbad552a956277ab3 |
| institution | Kabale University |
| issn | 2001-1326 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Medicine |
| spelling | doaj-art-7363500a87c6480dbad552a956277ab32025-01-25T04:00:38ZengWileyClinical and Translational Medicine2001-13262025-01-01151n/an/a10.1002/ctm2.70168Disturbed shear stress promotes atherosclerosis through TRIM21‐regulated MAPK6 degradation and consequent endothelial inflammationFeng Wang0Shu‐Yu Wang1Yue Gu2Shuai Luo3Ai‐Qun Chen4Chao‐Hua Kong5Wen‐Ying Zhou6Li‐Guo Wang7Zhi‐Mei Wang8Guang‐Feng Zuo9Xiao‐Fei Gao10Jun‐Jie Zhang11Shao‐Liang Chen12Division of Cardiology Nanjing First Hospital, Nanjing Medical University Nanjing ChinaDivision of Cardiology Nanjing First Hospital, Nanjing Medical University Nanjing ChinaDivision of Cardiology Nanjing First Hospital, Nanjing Medical University Nanjing ChinaDivision of Cardiology Nanjing First Hospital, Nanjing Medical University Nanjing ChinaDivision of Cardiology Nanjing First Hospital, Nanjing Medical University Nanjing ChinaDivision of Cardiology Nanjing First Hospital, Nanjing Medical University Nanjing ChinaDivision of Cardiology Nanjing First Hospital, Nanjing Medical University Nanjing ChinaKey Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Department of Cardiology, Sir Run Run Shaw Hospital, School of Medicine Zhejiang University Hangzhou ChinaDivision of Cardiology Nanjing First Hospital, Nanjing Medical University Nanjing ChinaDivision of Cardiology Nanjing First Hospital, Nanjing Medical University Nanjing ChinaDivision of Cardiology Nanjing First Hospital, Nanjing Medical University Nanjing ChinaDivision of Cardiology Nanjing First Hospital, Nanjing Medical University Nanjing ChinaDivision of Cardiology Nanjing First Hospital, Nanjing Medical University Nanjing ChinaAbstract Rationale Coronary artery plaques often develop in regions subjected to disturbed shear stress (DSS), yet the mechanisms underlying this phenomenon remain poorly understood. Our study aimed to elucidate the unknown role of MAPK6 in shear stress and plaque formation. Methods In vitro and in vivo experiments, RNA‐seq, CO‐IP and proteomic analysis, combined with single‐cell RNA‐seq datasets were used to reveal the upstream and downstream mechanisms involved. AAV‐MAPK6, ApoE−/−MAPK6flox/floxTEKCre mice and the CXCL12 neutraligand were used to confirm the beneficial effects of MAPK6 against atherosclerosis. Results Our study revealed a substantial decrease in MAPK6 protein levels in endothelial cells in response to DSS, both in vivo and in vitro, which was contingent on the binding of the ubiquitin ligase TRIM21 to MAPK6. Endothelium‐specific MAPK6 overexpression exerts antiatherosclerotic effects in ApoE−/− mice, elucidating the unexplored role of MAPK6 in atherosclerosis. Comprehensive RNA‐seq, integrated single‐cell mapping and further experiments unveiled the involvement of MAPK6 in inflammation through the EGR1/CXCL12 axis. ApoE−/−MAPK6flox/floxTEKCre mice finally confirmed that conditional MAPK6 knockout resulted in endothelial inflammation and significant increases in plaque areas. Notably, these effects could be reversed through the neutralization of CXCL12. Conclusions Our study illuminates the advantages of MAPK6 in decelerating plaque progression, highlighting the potential of safeguarding MAPK6 as a novel therapeutic strategy against atherosclerosis. Key points Disturbed flow activates the ubiquitin‒proteasome degradation pathway of MAPK6 in endothelial cells, which is contingent on the binding of the ubiquitin ligase TRIM21 to MAPK6. Endothelial MAPK6 has an advantageous impact on decelerating plaque progression. MAPK6 regulates endothelial inflammation via the EGR1/CXCL12 axis.https://doi.org/10.1002/ctm2.70168atherosclerosisendothelial inflammationMAPK6shear stressTRIM21 |
| spellingShingle | Feng Wang Shu‐Yu Wang Yue Gu Shuai Luo Ai‐Qun Chen Chao‐Hua Kong Wen‐Ying Zhou Li‐Guo Wang Zhi‐Mei Wang Guang‐Feng Zuo Xiao‐Fei Gao Jun‐Jie Zhang Shao‐Liang Chen Disturbed shear stress promotes atherosclerosis through TRIM21‐regulated MAPK6 degradation and consequent endothelial inflammation Clinical and Translational Medicine atherosclerosis endothelial inflammation MAPK6 shear stress TRIM21 |
| title | Disturbed shear stress promotes atherosclerosis through TRIM21‐regulated MAPK6 degradation and consequent endothelial inflammation |
| title_full | Disturbed shear stress promotes atherosclerosis through TRIM21‐regulated MAPK6 degradation and consequent endothelial inflammation |
| title_fullStr | Disturbed shear stress promotes atherosclerosis through TRIM21‐regulated MAPK6 degradation and consequent endothelial inflammation |
| title_full_unstemmed | Disturbed shear stress promotes atherosclerosis through TRIM21‐regulated MAPK6 degradation and consequent endothelial inflammation |
| title_short | Disturbed shear stress promotes atherosclerosis through TRIM21‐regulated MAPK6 degradation and consequent endothelial inflammation |
| title_sort | disturbed shear stress promotes atherosclerosis through trim21 regulated mapk6 degradation and consequent endothelial inflammation |
| topic | atherosclerosis endothelial inflammation MAPK6 shear stress TRIM21 |
| url | https://doi.org/10.1002/ctm2.70168 |
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