Carnosic acid protects against pressure overload-induced cardiac remodelling by inhibiting the AKT/GSK3β/NOX4 signalling pathway.

Abstract

Oxidative stress and apoptosis serve an important role in the development of pressure overload-induced cardiac remodelling. Carnosic acid (CA) has been found to exert antioxidant and anti-apoptotic effects. The present study investigated the underlying mechanism of CA protection and whether this effect was exerted against pressure overload-induced cardiac remodelling. Aortic banding (AB) surgery was performed to induce cardiac remodelling. Mice were randomly divided into four groups (n=15/group): i) Sham + vehicle; ii) sham + CA; iii) AB + vehicle; and iv) AB + CA. After 2 days of AB, 50 mg kg CA was administered orally for 12 days. Echocardiography, histological analysis and molecular biochemistry techniques were performed to evaluate the roles of CA. CA treatment decreased cardiac hypertrophy, fibrosis, oxidative stress and apoptosis in mice challenged with pressure overload. CA also decreased the cross-sectional area of cardiomyocytes and the mRNA and protein expression levels of hypertrophic markers. Furthermore, CA treatment decreased collagen deposition, α-smooth muscle actin expression and the mRNA and protein expression of various fibrotic markers. Additionally, CA reversed the AB-mediated increase in NAPDH oxidase (NOX) 2, NOX4 and 4-hydroxynonenal levels. The number of apoptotic cells was decreased following CA treatment following under conditions of pressure overload. CA also suppressed the activation of AKT and glycogen synthase kinase 3 β (GSK3β) in mice challenged with AB. The present results suggested that CA could inhibit pressure overload-induced cardiac hypertrophy and fibrosis by suppressing the AKT/GSK3β/NOX4 signalling pathway. Therefore, CA may be a promising therapy for cardiac remodelling.