Signal Transduction and Targeted Therapy | MAPK14 promotes smooth muscle cell degeneration in abdominal aortic aneurysm through transcriptional regulation

This study combines single-nucleus multi-omics sequencing, chromatin immunoprecipitation, and experimental validation to systematically reveal the critical transcriptional regulatory mechanism of MAPK14 in abdominal aortic aneurysm (AAA) formation. The research demonstrates that MAPK14 deletion activates the MYOCD/SRF/CArG transcriptional program and suppresses RUNX2 and MRTFA expression, thereby alleviating smooth muscle cell degeneration. These findings provide new therapeutic targets for AAA.

 

Literature Overview

The article titled 'MAPK14 converges on key transcriptional machinery to promote vascular smooth muscle cell degeneration in abdominal aortic aneurysm', published in Signal Transduction and Targeted Therapy, reviews and summarizes the molecular mechanisms by which MAPK14 regulates vascular smooth muscle cell (VSMC) degeneration in abdominal aortic aneurysm (AAA). Using a VSMC-specific knockout mouse model combined with single-nucleus RNA sequencing (snRNA-seq) and chromatin accessibility sequencing (snATAC-seq), the study reveals that MAPK14 deletion enhances SRF and MYOCD expression while suppressing VSMC dedifferentiation and degeneration, offering a mechanistic basis for targeted AAA therapies.

Background Knowledge

Abdominal aortic aneurysm (AAA) is a severe vascular disease characterized by progressive aortic wall dilation and structural degradation, for which no effective pharmacological interventions currently exist. VSMC degeneration is a central pathological process in AAA formation, marked by a transition from the contractile phenotype to dedifferentiated states involving inflammation, fibrosis, and apoptosis. This process is primarily driven by activation of pro-degenerative transcription factors such as RUNX2 and MRTFA, while being suppressed by the MYOCD/SRF/CArG transcriptional regulatory network. However, the upstream signaling mechanisms that coordinate the regulation of these transcription factors remain poorly understood. MAPK14 (p38α), a key kinase in VSMCs that responds to mechanical stress, oxidative stress, and inflammatory signals, has been linked to various vascular remodeling-related diseases. This study further demonstrates its role in AAA pathogenesis by modulating the transcriptional factor network that governs VSMC fate, providing a molecular foundation for MAPK14-targeted therapeutic strategies.

 

 

Research Methods and Experiments

The research team generated smooth muscle cell-specific Mapk14 knockout (KO) mice and compared them with wild-type (WT) mice after 7 days of Ang II infusion. Tissues were collected for analysis. Single-nucleus RNA sequencing (snRNA-seq) and single-nucleus ATAC sequencing (snATAC-seq) were employed to investigate transcriptomic and epigenomic changes in VSMCs from KO and WT aortas. ChIP-seq and Western blot analyses were used to validate the binding activity of transcription factors, while functional assays assessed VSMC apoptosis, proliferation, and inflammatory status. The study also evaluated the relationship between MRTFA protein stability and MAPK14 deletion, and verified the regulatory mechanism of MYOCD/SRF/CArG on Bcl2 expression.

Key Conclusions and Perspectives

• Mapk14 deletion significantly inhibits Ang II-induced VSMC degeneration, increasing the proportion of contractile VSMCs while decreasing fibrotic and inflammatory phenotypes.
• SRF and MYOCD expression is upregulated in knockout mice, and the chromatin accessibility at CArG motifs in promoter regions of contractile genes is enhanced.
• MAPK14 deletion leads to downregulation of RUNX2 and its target genes, including Col1a1 and Col3a1, thereby reducing fibrosis and inflammation.
• The MYOCD/SRF/CArG transcriptional program is activated in KO mice, with Bcl2 identified as a novel target gene involved in anti-apoptotic regulation.
• MAPK14 deletion enhances ubiquitin-proteasome-mediated degradation of MRTFA, reducing its protein levels, suggesting that the MAPK14-MRTFA signaling axis contributes to VSMC dedifferentiation.
• Usp10 expression is downregulated in KO mice, and its deletion mimics the KO phenotype, indicating that MAPK14 regulates MRTFA protein stability through USP10.

Research Significance and Prospects

This study systematically elucidates the role of MAPK14 in orchestrating transcriptional factor networks during AAA development, offering novel insights for targeted therapies aimed at VSMC degeneration. Future studies may assess the efficacy of MAPK14 inhibitors in preclinical models, evaluate their regulation of downstream effectors such as SRF and RUNX2, and explore the functional roles of this pathway in other vascular pathologies. Additionally, the interaction between MAPK14 and USP10 may provide new intervention targets for modulating protein homeostasis.

 

 

Conclusion

This study integrates single-nucleus transcriptomic and epigenomic analyses with ChIP and functional validation to reveal the critical role of MAPK14 in regulating VSMC phenotypic transitions and AAA formation. It demonstrates that MAPK14 deletion activates the MYOCD/SRF/CArG transcriptional program, suppresses VSMC dedifferentiation, and reduces apoptosis through enhanced Bcl2 expression. Furthermore, MAPK14 regulates MRTFA protein stability via modulation of Usp10, offering new targets for AAA molecular mechanism research and therapeutic interventions. These findings deepen our understanding of AAA pathogenesis and provide a foundation for developing therapeutic strategies targeting MAPK14, SRF, or RUNX2. Future work should focus on the functional roles of the MAPK14 signaling axis in various vascular diseases and assess its feasibility as a therapeutic target.

 

Xiaoliang Wu, Chunhui Wang, Nestor Ishimwe, Joseph M Miano, and Xiaochun Long. MAPK14 converges on key transcriptional machinery to promote vascular smooth muscle cell degeneration in abdominal aortic aneurysm. Signal Transduction and Targeted Therapy.