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
Affiliations
Ping Gao
Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA
Pan Gao
Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA, USA
Jinjing Zhao
Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA
Shengshuai Shan
Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA, USA
Wei Luo
Michael E. DeBakey Department of Surgery, Baylor College of Medicine, One Baylor Plaza, BCM 390, Houston, TX, USA
Orazio J. Slivano
Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA, USA
Wei Zhang
Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA, USA
Akiko Tabuchi
Laboratory of Molecular Neurobiology, Graduate School of Medicine & Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
Scott A. LeMaire
Michael E. DeBakey Department of Surgery, Baylor College of Medicine, One Baylor Plaza, BCM 390, Houston, TX, USA
Lars Maegdefessel
Department for Vascular and Endovascular Surgery, Klinikum Rechts der Isar, Technical University Munich, Germany; German Center for Cardiovascular Research (DZHK, Partner Site Munich), Germany; Department of Medicine, Karolinska Institute, Stockholm, Sweden
Ying H. Shen
Michael E. DeBakey Department of Surgery, Baylor College of Medicine, One Baylor Plaza, BCM 390, Houston, TX, USA
Joseph M. Miano
Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA, USA
Harold A. Singer
Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA
Xiaochun Long
Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA; Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA, USA; Corresponding author. Vascular Biology Center, Medical College of Georgia at Augusta University, 1460 Laney Walker Blvd, Augusta, GA, USA.
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.
