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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 inSmad3 (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)–associatedmiR-21 was higher in TAAD lesions. We hypothesize that downregulation ofmiR-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 thatmiR-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 ofSmad7 with lentivirus prevented AngII-induced TAAD formation in S3+/− 21−/− mice.Conclusions— Our study demonstrated thatmiR-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.

arteriosclerosis, thrombosis, and vascular biology

MicroRNA-21 Knockout Exacerbates Angiotensin II–Induced Thoracic Aortic Aneurysm and Dissection in Mice With Abnormal Transforming Growth Factor-β–SMAD3 Signaling