MRTF-A promotes angiotensin II-induced inflammatory response and aortic dissection in mice
MRTF-A promotes angiotensin II-induced inflammatory response and aortic dissection in mice
复制标题
DOI：
10.1371/journal.pone.0229888
复制
发表时间：
2020-03-24
期刊：
影响因子：
3.7
通讯作者：
Fukumoto, Yoshihiro
中科院分区：
文献类型：
--
作者：
Ito, Sohei;Hashimoto, Yohei;Fukumoto, Yoshihiro
主动脉夹层（AD）是急性主动脉综合征的主要原因，由于主动脉壁的破坏，死亡率很高。虽然最近的研究表明炎症在AD的发病机制中起着关键作用，但炎症反应是如何启动的还不清楚。在这里，我们表明，心肌相关转录因子A（MRTF-A），体液和机械应力的信号转导，在AD的发病机制中起着重要的作用，在小鼠模型。通过连续输注血管紧张素II（AngII）诱导MRTF-A表达并在4天内引起AD来创建AD小鼠模型。Mrtfa基因的系统性缺失导致AD发展的显著抑制。转录组和基因注释富集分析显示，血管紧张素II输注1天引起促炎和促凋亡反应前AD的发展，这是抑制Mrtfa删除。AngII输注1天诱导促炎反应，如通过IL 6、Tnf和Ccl 2的表达所证明的，以及主动脉壁细胞的凋亡，如通过TUNEL染色所检测的，以MRTF-A依赖的方式。AngII输注期间CCG-203971对MRTF-A的药理学抑制部分抑制了AD表型，表明MRTF-A的急性抑制可有效预防主动脉壁破坏。这些结果表明，MRTF-A将AngII激发的应激转导为促炎和促凋亡反应，最终导致AD的发展。干预这一途径可能是一种潜在的治疗策略。
Aortic dissection (AD) is a major cause of acute aortic syndrome with high mortality due to the destruction of aortic walls. Although recent studies indicate the critical role of inflammation in the disease mechanism of AD, it is unclear how inflammatory response is initiated. Here, we demonstrate that myocardin-related transcription factor A (MRTF-A), a signal transducer of humoral and mechanical stress, plays an important role in pathogenesis of AD in a mouse model. A mouse model of AD was created by continuous infusion of angiotensin II (AngII) that induced MRTF-A expression and caused AD in 4 days. Systemic deletion of Mrtfa gene resulted in a marked suppression of AD development. Transcriptome and gene annotation enrichment analyses revealed that AngII infusion for 1 day caused pro-inflammatory and pro-apoptotic responses before AD development, which were suppressed by Mrtfa deletion. AngII infusion for 1 day induced pro-inflammatory response, as demonstrated by expressions of Il6, Tnf, and Ccl2, and apoptosis of aortic wall cells, as detected by TUNEL staining, in an MRTF-A-dependent manner. Pharmacological inhibition of MRTF-A by CCG-203971 during AngII infusion partially suppressed AD phenotype, indicating that acute suppression of MRTF-A is effective in preventing the aortic wall destruction. These results indicate that MRTF-A transduces the stress of AngII challenge to the pro-inflammatory and proapoptotic responses, ultimately leading to AD development. Intervening this pathway may represent a potential therapeutic strategy.