OS 36-07 TREATMENT WITH APELIN-13 PREVENTS PRESSURE OVERLOAD-INDUCED AORTIC ADVENTITIAL REMODELING AND FIBROSIS IN HYPERTENSIVE RATS WITH TAC

Abstract

Objective: The Apelin/APJ system has recently been implicated in pathologies of hypertension. However, little was elucidated upon effects of Apelin on vascular adventitial remodeling progression. Here, we examined regulatory roles of Apelin in pressure overload-induced adventitial remodeling and fibrosis in hypertensive rats. Design and Method: The male Sprague–Dawley rats were performed with transverse aortic constriction (TAC). The rats with TAC were randomized to daily deliver either pyroglutamyl Apelin-13 (50 μg/kg) or saline for 4 weeks. Results: Histomorphometric analysis by HE and Masson trichrome staining revealed increased medial and adventitial thicknesses, especially in the adventitia, in ascending aortas in rats with TAC when compared with the sham-operated rats. Downregulation of APJ receptor and elevations in systolic blood pressure, phosphorylated mTOR and ERK1/2 levels were observed in hypertensive rats with TAC. Pressure overload-mediated by TAC led to marked increases in heart weight (HW), HW/body weight ratio, malonyldialdehyde (MDA) contents and aortic fibrosis in the hypertensive rats with enhanced activation of NADPH oxidase activity. The pressure overload-mediated pathological adventitial remodeling was strikingly rescued by Apelin-13 supplementation, associated with attenuation of aortic fibrosis and reduced mRNA expression of TGF-ß1 and collagen I. In cultured rat adventitial fibroblasts, exposure with Ang II (100 nmol L−1) resulted in obvious increases in MDA, phosphorylated levels of mTOR and ERK1/2 and mRNA levels of TGF-ß1, collagen I and fibronectin 1, which were dramatically prevented by Apelin-13 (100 nmol L−1) or mTOR inhibitor rapamycin (10 μmol L−1). However, Apelin-13 had no effect on collagen III levels. Conclusions: Our results demonstrate the importance of Apelin-13 in amelioration of aortic oxidative stress, adventitial remodeling and fibrosis in hypertensive rats with TAC via modulation of the mTOR/ERK signaling, thus indicating potential therapeutic strategies by enhancing Apelin/APJ action for preventing hypertensive vascular adventitial remodeling and fibrosis and pressure overload-associated cardiovascular disorders.