Effects of Angiotensin-(1-7) on the Proliferation and Collagen Synthesis of Arginine Vasopressin-stimulated Rat Cardiac Fibroblasts: Role of Mas Receptor-Calcineurin-NF-κB Signaling Pathway

Interstitial fibrosis is a common pathological change in various heart diseases, especially cardiac hypertrophy. Arginine vasopressin (AVP), one of the hallmarks of heart failure, exhibits a profibrotic effect by promoting the proliferation and differentiation of cardiac fibroblasts (CFs). In contrast, angiotensin-(1-7) [Ang-(1-7)] was reported to be beneficial for cardiac remodeling by its antifibrotic effect. To evaluate the effect of Ang-(1-7) on AVP-stimulated CFs and the subsequent signaling molecules involved, CFs isolated from neonatal rat hearts were incubated with AVP and treated with or without Ang-(1-7). Cell proliferation, cell cycle, collagen production, and related cellular signaling molecules were then assessed. The results showed that Ang-(1-7) dose-dependently inhibited cell proliferation and collagen production in AVP-stimulated CFs. In addition, Ang-(1-7) also significantly suppressed calcineurin activity in a dose-dependent manner in AVP-stimulated CFs, which was associated with reduced collagen production. Accordingly, the nuclear translocation and transcriptional activity of nuclear factor-kappa B (NF-B), downstream signal of calcineurin, were also notably restrained by Ang-(1-7) in AVP-stimulated CFs. Furthermore, the inhibitory effect of Ang-(1-7) on AVP-activated calcineurin-NF-B signaling was completely reversed by the Mas receptor antagonist A-799. These findings suggest that Ang-(1-7) exerts an antifibrotic effect by inhibiting AVP-stimulated CF proliferation and collagen synthesis by inactivating Mas receptor-calcineurin-NF-B signaling pathway.