Resveratrol ameliorates myocardial fibrosis by inhibiting ROS/ERK/TGF-β/periostin pathway in STZ-induced diabetic mice

Abstract

Background: Myocardial fibrosis is an essential hallmark of diabetic cardiomyopathy (DCM) contributing to cardiac dysfunctions. Resveratrol, an antioxidant, exerts its anti-fibrotic effect via inhibition of oxidative stress, while the underlying molecular mechanism remains largely elusive. Periostin, a fibrogenesis matricellular protein, has been shown to be associated with oxidative stress. In the present study, we investigated the role of periostin in anti-fibrotic effect of resveratrol in streptozocin (STZ)-induced diabetic heart and the underlying mechanisms. Methods: Diabetic mice were induced by STZ injection. After treatment with resveratrol (5 or 25 mg/kg/day i.g) or Saline containing 0.5 % carboxymethyl cellulose (CMC) for 2 months, the hearts were detected for oxidative stress and cardiac fibrosis using western blot, Masson's trichrome staining and Dihydroethidium (DHE) staining. In in vitro experiments, proliferation and differentiation of fibroblasts under different conditions were investigated through western blot, 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assay and immunofluorescence staining. Results: Administration of resveratrol significantly mitigated oxidative level, interstitial fibrosis and expressions of related proteins in STZ-induced diabetic hearts. In in vitro experiments, resveratrol exhibited anti-proliferative effect on primary mouse cardiac fibroblasts via inhibiting reactive oxygen species (ROS)/extracellular regulated kinase (ERK) pathway and ameliorated myofibroblast differentiation via suppressing ROS/ERK/ transforming growth factor β (TGF-β)/periostin pathway. Conclusion: Increased ROS production, activation of ERK/TGF-β/periostin pathway and myocardial fibrosis are important events in DCM. Alleviated ROS genesis by resveratrol prevents myocardial fibrosis by regulating periostin related signaling pathway. Thus, inhibition of ROS/periostin may represent a novel approach for resveratrol to reverse fibrosis in DCM.