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 (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. 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.
CITATION STYLE
Huang, X., Yue, Z., Wu, J., Chen, J., Wang, S., Wu, J., … Xia, J. (2018). MicroRNA-21 knockout exacerbates angiotensin II–induced thoracic aortic aneurysm and dissection in mice with abnormal transforming growth factor-β–SMAD3 signaling. Arteriosclerosis, Thrombosis, and Vascular Biology, 38(5), 1086–1101. https://doi.org/10.1161/ATVBAHA.117.310694
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