MicroRNA-21 Knockout Exacerbates Angiotensin II-Induced Thoracic Aortic Aneurysm and Dissection in Mice With Abnormal Transforming Growth Factor--SMAD3 Signaling
MicroRNA-21 Knockout Exacerbates Angiotensin II-Induced Thoracic Aortic Aneurysm and Dissection in Mice With Abnormal Transforming Growth Factor--SMAD3 Signaling
复制标题
MicroRNA-21 敲除会加剧转化生长因子-βSMAD3 信号异常小鼠的血管紧张素 II 诱导的胸主动脉瘤和夹层
DOI：
10.1161/atvbaha.117.310694
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发表时间：
2018-05-01
影响因子：
8.7
通讯作者：
Xia, Jiahong
中科院分区：
文献类型：
--
作者：
Huang, Xiaofan;Yue, Zhang;Xia, Jiahong
目的胸主动脉瘤和夹层（TAAD）是严重的血管疾病。血管平滑肌细胞中转化生长因子（TGF-β）信号传导功能障碍和血管紧张素II（AngII）水平升高与TAAD的发生有关。在这项研究中，我们调查了这两个因素是否导致TAAD的小鼠模型，并探讨了使用microRNA-21（miR-21）治疗TAAD.Approach和结果TAAD的Smad 3（母亲对decapentaplegic同源3）杂合子（S3（+/-））小鼠输注AngII。我们发现，p-ERK（磷酸化细胞外调节蛋白激酶）和p-JNK（磷酸化c-Jun N-末端激酶）相关的miR-21在TAAD病变中较高。我们假设下调miR-21可减轻TAAD的形成。然而，Smad 3（+/-）：miR-21（-/-）（S3（+/-）21（-/-））小鼠在AngII输注后表现出明显的TAAD形成。血管壁扩张，主动脉破裂发生在23天内的AngII输注。然后，我们检查了经典和非经典TGF-信号传导，发现S3（+/-）小鼠中的miR-21敲除增加了SMAD 7并抑制了经典TGF-信号传导。缺乏TGF-β信号的血管平滑肌细胞倾向于从收缩型转变为合成型。结论miR-21基因敲除可加重AngII诱导的TAAD的形成，其机制可能与TGF-β 1信号通路功能障碍有关。针对TAAD的治疗策略应考虑与TGF-信号转导改变相关的意外副作用。
Objective Thoracic aortic aneurysm and dissection (TAAD) are severe vascular conditions. Dysfunctional transforming growth factor- (TGF-) 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.Approach and Results 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- signaling and found that miR-21 knockout in S3(+/-) mice increased SMAD7 and suppressed canonical TGF- signaling. Vascular smooth muscle cells lacking TGF- 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.Conclusions Our study demonstrated that miR-21 knockout exacerbated AngII-induced TAAD formation in mice, which was associated with TGF- signaling dysfunction. Therapeutic strategies targeting TAAD should consider unexpected side effects associated with alterations in TGF- signaling.