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

Summary

Disturbed shear stress triggers TRIM21-mediated ubiquitin–proteasome degradation of endothelial MAPK6, amplifying inflammation (via EGR1/CXCL12) and accelerating atherosclerosis; preserving endothelial MAPK6 attenuated plaque progression in vivo. This identifies MAPK6 as a mechano-regulated anti-atherosclerotic node.

Key Findings

• Disturbed shear stress reduced endothelial MAPK6 via TRIM21-dependent ubiquitin–proteasome degradation in vitro and in vivo.
• Endothelium-specific MAPK6 overexpression decreased atherosclerotic plaque progression in ApoE-deficient models.
• MAPK6 modulated endothelial inflammation through the EGR1/CXCL12 axis.

Clinical Implications

While preclinical, targeting TRIM21–MAPK6 signaling or stabilizing MAPK6 could complement lipid-lowering by directly mitigating flow-induced endothelial inflammation in high-risk vascular regions.

Limitations

• Details on animal model numbers and effect sizes are not provided in the abstract
• Translational relevance to human vascular beds and potential off-target effects require validation

Future Directions

Develop TRIM21–MAPK6 modulators, test MAPK6 stabilization in large-animal models and human tissues, and assess synergy with lipid-lowering and anti-inflammatory therapies.