Ascending aortic adventitial remodeling and fibrosis are ameliorated with Apelin-13 in rats after TAC via suppression of the miRNA-122 and LGR4-β-catenin signaling

• Published in: Peptides (New York, N.Y. : 1980) N.Y. : 1980), 2016-12, Vol.86, p.85-94
• Main Authors: Xu, Ran, Zhang, Zhen-Zhou, Chen, Lai-Jiang, Yu, Hui-Min, Guo, Shu-Jie, Xu, Ying-Le, Oudit, Gavin Y., Zhang, Yan, Chang, Qing, Song, Bei, Chen, Dong-Rui, Zhu, Ding-Liang, Zhong, Jiu-Chang
• Format: Article
• Language: English
• Subjects: Adventitia - pathology; Adventitial fibrosis; Angiotensin II; Animals; Aorta - pathology; Aortic Aneurysm, Thoracic - metabolism; Aortic Aneurysm, Thoracic - pathology; Aortic remodeling; Apelin; beta Catenin - metabolism; Cardiomegaly - metabolism; Cells, Cultured; Fibrosis; Intercellular Signaling Peptides and Proteins - pharmacology; Intercellular Signaling Peptides and Proteins - physiology; LGR4; Male; MicroRNAs - metabolism; Myocardium - metabolism; Myocardium - pathology; Pressure overload; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled - metabolism; Transcription Factors - metabolism; Vascular Remodeling; Ventricular Remodeling; Wnt Signaling Pathway
• ISSN: 0196-9781; 1873-5169
• DOI: 10.1016/j.peptides.2016.10.005

•Reduction of Apelin and elevation of miRNA-122 are observed in the ascending aortas of rats after transverse aortic constriction.•Apelin has anti-fibrotic properties with normalization of TAC-induced aortic activation of the LGR4/β-catenin signaling.•Treatment with Apelin-13 and miRNA-122 inhibitor prevents angiotensin II-mediated the LGR4/β-catenin activation and cellular migration promotion. Apelin has been proved to be a critical mediator of vascular function and homeostasis. Here, we investigated roles of Apelin in aortic remodeling and fibrosis in rats with transverse aortic constriction (TAC). Male Sprague-Dawley rats were subjected to TAC and then randomized to daily deliver Apelin-13 (50μg/kg) or angiotensin type 1 receptor (AT1) blocker Irbesartan (50mg/kg) for 4 weeks. Pressure overload resulted in myocardial hypertrophy, systolic dysfunction, aortic remodeling and adventitial fibrosis with reduced levels of Apelin in ascending aortas of rat after TAC compared with sham-operated group. These changes were associated with marked increases in levels of miRNA-122, TGFβ1, CTGF, NFAT5, LGR4, and β-catenin. More importantly, Apelin and Irbesartan treatment strikingly prevented TAC-mediated aortic remodeling and adventitial fibrosis in pressure overloaded rats by blocking AT1 receptor and miRNA-122 levels and repressing activation of the CTGF-NFAT5 and LGR4-β-catenin signaling. In cultured primary rat adventitial fibroblasts, exposure to angiotensin II (100nmolL−1) led to significant increases in cellular migration and levels of TGFβ1, CTGF, NFAT5, LGR4 and β-catenin, which were effectively reversed by pre-treatment with Apelin (100nmolL−1) and miRNA-122 inhibitor (50nmolL−1). In conclusion, Apelin counterregulated against TAC-mediated ascending aortic remodeling and angiotensin II-induced promotion of cellular migration by blocking AT1 receptor and miRNA-122 levels and preventing activation of the TGFβ1-CTGF-NFAT5 and LGR4-β-catenin signaling, ultimately contributing to attenuation of aortic adventitial fibrosis. Our data point to Apelin as an important regulator of aortic remodeling and adventitial fibrosis and a promising target for vasoprotective therapies.