| First Author | Huang X | Year | 2018 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 38 |
| Issue | 5 | Pages | 1086-1101 |
| PubMed ID | 29519942 | Mgi Jnum | J:285163 |
| Mgi Id | MGI:6385478 | Doi | 10.1161/ATVBAHA.117.310694 |
| Citation | Huang X, et al. (2018) MicroRNA-21 Knockout Exacerbates Angiotensin II-Induced Thoracic Aortic Aneurysm and Dissection in Mice With Abnormal Transforming Growth Factor-beta-SMAD3 Signaling. Arterioscler Thromb Vasc Biol 38(5):1086-1101 |
| abstractText | OBJECTIVE: Thoracic aortic aneurysm and dissection (TAAD) are severe vascular conditions. Dysfunctional transforming growth factor-beta (TGF-beta) 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-beta signaling and found that miR-21 knockout in S3(+/-) mice increased SMAD7 and suppressed canonical TGF-beta signaling. Vascular smooth muscle cells lacking TGF-beta 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-beta signaling dysfunction. Therapeutic strategies targeting TAAD should consider unexpected side effects associated with alterations in TGF-beta signaling. |
