MKL1 cooperates with p38MAPK to promote vascular senescence, inflammation, and abdominal aortic aneurysm

• Published in: Redox biology Vol. 41; p. 101903
• Main Authors: Gao, Ping, Gao, Pan, Zhao, Jinjing, Shan, Shengshuai, Luo, Wei, Slivano, Orazio J., Zhang, Wei, Tabuchi, Akiko, LeMaire, Scott A., Maegdefessel, Lars, Shen, Ying H., Miano, Joseph M., Singer, Harold A., Long, Xiaochun
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2021; Elsevier
• Subjects: Angiotensin II; Animals; Aortic aneurysm; Aortic Aneurysm, Abdominal; Disease Models, Animal; Inflammation; Medicin och hälsovetenskap; Mice; Mice, Inbred C57BL; Mice, Knockout; MKL1; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; p38 Mitogen-Activated Protein Kinases; p38MAPK; Research Paper; Senescence; Trans-Activators; Senescence; Inflammation; Aortic aneurysm; p38MAPK; MKL1
• DOI: 10.1016/j.redox.2021.101903
• ISSN: 2213-2317

Abdominal aortic aneurysm (AAA) is a catastrophic disease with little effective therapy. Myocardin related transcription factor A (MRTFA, MKL1) is a multifaceted transcription factor, regulating diverse biological processes. However, a detailed understanding of the mechanistic role of MKL1 in AAA has yet to be elucidated. In this study, we showed induced MKL1 expression in thoracic and abdominal aneurysmal tissues, respectively in both mice and humans. MKL1 global knockout mice displayed reduced AAA formation and aortic rupture compared with wild-type mice. Both gene deletion and pharmacological inhibition of MKL1 markedly protected mice from aortic dissection, an early event in Angiotensin II (Ang II)-induced AAA formation. Loss of MKL1 was accompanied by reduced senescence/proinflammation in the vessel wall and cultured vascular smooth muscle cells (VSMCs). Mechanistically, a deficiency in MKL1 abolished AAA-induced p38 mitogen activated protein kinase (p38MAPK) activity. Similar to MKL1, loss of MAPK14 (p38α), the dominant isoform of p38MAPK family in VSMCs suppressed Ang II-induced AAA formation, vascular inflammation, and senescence marker expression. These results reveal a molecular pathway of AAA formation involving MKL1/p38MAPK stimulation and a VSMC senescent/proinflammatory phenotype. These data support targeting MKL1/p38MAPK pathway as a potential effective treatment for AAA. [Display omitted] •MKL1 expression is induced in both thoracic and abdominal aneurysmal tissues.•Genetic ablation and pharmacological inhibition of MKL1 protect mice from aortic dissection and AAA induced by Ang II.•Depletion of MKL1 in mice suppresses Ang II-induced vascular inflammation and senescence.•Depletion of MKL1 blunts the activation of p38MAPK and STAT3 pathways.•Loss of MAPK14 in VSMCs suppresses Ang II-induced AAA formation, vascular inflammation, and senescence marker expression.