血管紧张素II
基因沉默
转化生长因子
下调和上调
基因剔除小鼠
血管平滑肌
信号转导
癌症研究
转化生长因子β
表型转换
小RNA
MAPK/ERK通路
医学
内科学
内分泌学
生物
化学
细胞生物学
受体
生物化学
基因
平滑肌
作者
Xintang Huang,Yue Zhang,Jia Wu,Jiuling Chen,Sihua Wang,Jie Wu,Linyun Ren,Anchen Zhang,Peng Deng,Ke Wang,Chuangyan Wu,Xiangchao Ding,Ping Ye,Jiahong Xia
标识
DOI:10.1161/atvbaha.117.310694
摘要
Thoracic aortic aneurysm and dissection (TAAD) are severe vascular conditions. Dysfunctional transforming growth factor-β (TGF-β) signaling in vascular smooth muscle cells and elevated angiotensin II (AngII) levels are implicated in the development of TAAD. In this study, we investigated whether these 2 factors lead to TAAD in a mouse model and explored the possibility of using microRNA-21 (miR-21) for the treatment of TAAD.TAAD was developed in Smad3 (mothers against decapentaplegic homolog 3) heterozygous (S3+/-) mice infused with AngII. We found that p-ERK (phosphorylated extracellular regulated protein kinases)- and p-JNK (phosphorylated c-Jun N-terminal kinase)-associated miR-21 was higher in TAAD lesions. We hypothesize that downregulation of miR-21 mitigate TAAD formation. However, Smad3+/-:miR-21-/- (S3+/-21-/-) mice exhibited conspicuous TAAD formation after AngII infusion. The vascular wall was dilated, and aortic rupture occurred within 23 days during AngII infusion. We then examined canonical and noncanonical TGF-β signaling and found that miR-21 knockout in S3+/- mice increased SMAD7 and suppressed canonical TGF-β signaling. Vascular smooth muscle cells lacking TGF-β signals tended to switch from a contractile to a synthetic phenotype. The silencing of Smad7 with lentivirus prevented AngII-induced TAAD formation in S3+/-21-/- mice.Our study demonstrated that miR-21 knockout exacerbated AngII-induced TAAD formation in mice, which was associated with TGF-β signaling dysfunction. Therapeutic strategies targeting TAAD should consider unexpected side effects associated with alterations in TGF-β signaling.
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