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/floxTEK^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/floxTEK^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.

Pathological cardiac remodeling is a significant contributor to heart failure and mortality. Studies have demonstrated that extracellular signal regulated kinase 3 (ERK3) in cardiac fibroblasts aggravates pressure overload-evoked pathological cardiac remodeling via mitogen activated protein kinase-activated protein kinase-5 (MK5). However, myocardial ERK3 does not activate MK5, thus the role of myocardial ERK3 remains unclear. Through in vivo and in vitro experiments, we revealed that myocardial ERK3 expression increases under pressure overload and the protein accumulates significantly in the nucleus. Using cardiomyocyte-specific Erk3 -deficient mice, neonatal rat cardiomyocytes and adult mouse cardiomyocytes, we found that cardiomyocyte-specific Erk3 deficiency ameliorated pressure overload-induced pathological cardiac remodeling in vivo. Co-immunoprecipitation, mass spectrometry, and single nucleus RNA sequencing were used to analyse for the nuclear translocation and downstream signaling mechanisms of ERK3. Specifically, pressure overload enhances the binding of Aly/REF export factor (ALY) to ERK3, resulting in the truncation of the ERK3 C-terminal and its subsequent nuclear translocation to activate the thioredoxin-interacting protein (TXNIP)/NOD-like receptor thermal protein domain associated protein 3 (NLRP3) pathway through the expression of the splicing factor proline and glutamine rich (SFPQ). To screen for targeted drugs, we conducted a virtual screening and identified estrone sulfate as an inhibitor of ALY to counteract hypertrophic effects. Collectively, our findings indicate that estrone sulfate functions as a novel inhibitor of the ALY-ERK3 signaling pathway, potentially serving as a promising therapeutic candidate for the management of pathological cardiac remodeling.

Endothelial dysfunction persisting after glucose normalization, termed metabolic memory, constitutes a primary driver of diabetic vascular complications, y