LAUSR

Objective— Thoracic aortic aneurysm and dissection (TAAD) are severe vascular conditions. Dysfunctional transforming growth factor-&bgr; (TGF-&bgr;) 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-&bgr; signaling and found that miR-21 knockout in S3+/− mice increased SMAD7 and suppressed canonical TGF-&bgr; signaling. Vascular smooth muscle cells lacking TGF-&bgr; 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-&bgr; signaling dysfunction. Therapeutic strategies targeting TAAD should consider unexpected side effects associated with alterations in TGF-&bgr; signaling.