肌钙蛋白
血管平滑肌
炎症
促炎细胞因子
p38丝裂原活化蛋白激酶
血清反应因子
腹主动脉瘤
血管紧张素II
转录因子
细胞生物学
医学
癌症研究
生物
免疫学
激酶
内科学
MAPK/ERK通路
动脉瘤
基因
外科
受体
平滑肌
生物化学
作者
Ping Gao,Pan Gao,Jinjing Zhao,Shengshuai Shan,Wei Luo,Orazio J. Slivano,Wei Zhang,Akiko Tabuchi,Scott A. LeMaire,Lars Mäegdefessel,Ying H. Shen,Joseph M. Miano,Harold A. Singer,Xiaochun Long
出处
期刊:Redox biology
[Elsevier]
日期:2021-02-21
卷期号:41: 101903-101903
被引量:38
标识
DOI:10.1016/j.redox.2021.101903
摘要
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.
科研通智能强力驱动
Strongly Powered by AbleSci AI