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

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 (50 mu g/kg) or angiotensin type 1 receptor (AT1) blocker Irbesartan (50 mg/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,TGF beta 1, CTGF, NFAT5, LGR4, and beta-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-beta-catenin signaling. In cultured primary rat adventitial fibroblasts, exposure to angiotensin II (100 nmol L-1) led to significant increases in cellular migration and levels of TGFI31, CTGF, NFAT5, LGR4 and beta-catenin, which were effectively reversed by pre-treatment with Apelin (100 nmol L-1) and miRNA-122 inhibitor (50 nmol L-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 TGF beta 1-CTGF-NFAT5 and LGR4-beta-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. (C) 2016 Elsevier Inc. All rights reserved.