Disturbed shear stress promotes atherosclerosis through TRIM21-regulated MAPK6 degradation and consequent endothelial inflammation.

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(-/-)MAPK6(flox/flox)TEK(Cre) 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(-/-)MAPK6(flox/flox)TEK(Cre) 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.