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

Ping Gao, Pan Gao, Jinjing Zhao, Shengshuai Shan, Wei Luo, Orazio J. Slivano, Wei Zhang, Akiko Tabuchi, Scott A. LeMaire, Lars Maegdefessel, Ying H. Shen, Joseph M. Miano, Harold A. Singer, Xiaochun Long

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article number101903
JournalRedox Biology
Volume41
DOIs
StatePublished - May 2021

Keywords

  • Aortic aneurysm
  • Inflammation
  • MKL1
  • Senescence
  • p38MAPK

ASJC Scopus subject areas

  • Organic Chemistry
  • Clinical Biochemistry

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