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 () for the treatment of TAAD. miR-21
APPROACH AND RESULTS: TAAD was developed in(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)-associatedwas higher in TAAD lesions. We hypothesize that downregulation ofmitigate TAAD formation. However,(S321) 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 thatknockout in S3mice 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 ofwith lentivirus prevented AngII-induced TAAD formation in S321mice. Smad3miR-21miR-21Smad3:miR-21miR-21Smad7 +/-+/--/-+/--/-+/-+/--/-
CONCLUSIONS: Our study demonstrated thatknockout 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. miR-21
