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

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 38; no. 5; pp. 1086 - 1101
• Main Authors: Huang, Xiaofan, Yue, Zhang, Wu, Jia, Chen, Jiuling, Wang, Sihua, Wu, Jie, Ren, Linyun, Zhang, Anchen, Deng, Peng, Wang, Ke, Wu, Chuangyan, Ding, Xiangchao, Ye, Ping, Xia, Jiahong
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 01.05.2018
• Subjects: Aneurysm, Dissecting - chemically induced; Aneurysm, Dissecting - genetics; Aneurysm, Dissecting - metabolism; Aneurysm, Dissecting - prevention & control; Angiotensin II; Animals; Aorta, Thoracic - metabolism; Aorta, Thoracic - pathology; Aortic Aneurysm, Thoracic - chemically induced; Aortic Aneurysm, Thoracic - genetics; Aortic Aneurysm, Thoracic - metabolism; Aortic Aneurysm, Thoracic - prevention & control; Aortic Rupture - chemically induced; Aortic Rupture - genetics; Aortic Rupture - metabolism; Aortic Rupture - prevention & control; Cells, Cultured; Dilatation, Pathologic; Disease Models, Animal; Disease Progression; Extracellular Signal-Regulated MAP Kinases; Genetic Predisposition to Disease; JNK Mitogen-Activated Protein Kinases - metabolism; Male; Mice, Inbred C57BL; Mice, Knockout; MicroRNAs - genetics; MicroRNAs - metabolism; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - pathology; Myocytes, Smooth Muscle - metabolism; Myocytes, Smooth Muscle - pathology; Phenotype; Phosphorylation; Signal Transduction; Smad3 Protein - deficiency; Smad3 Protein - genetics; Smad7 Protein - genetics; Smad7 Protein - metabolism; Transforming Growth Factor beta - metabolism; microRNAs; smooth muscle cell; thoracic aortic aneurysm and dissection; transforming growth factors-β; angiotensin II
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/ATVBAHA.117.310694

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 (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 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 S321 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.