MicroRNA-21 Knockout Exacerbates Angiotensin II–Induced Thoracic Aortic Aneurysm and Dissection in Mice With Abnormal Transforming Growth Factor-β–SMAD3 Signaling
Xiaofan Huang, Zhang Yue, Jia Wu, Jiuling Chen, Sihua Wang, Jie Wu, Linyun Ren, Anchen Zhang, Peng Deng, Ke Wang, Chuangyan Wu, Xiangchao Ding, Ping Ye, Jiahong XiaArteriosclerosis, Thrombosis, and Vascular Biology2018
Objective—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. Approach and Results—TAAD was developed in Smad3 heterozygous (S3+/− ) mice infused with AngII. We found that p-ERK– and p-JNK–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. Conclusions—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.