Inhibitory effects of oxymatrine on TGF‑β1‑induced proliferation and abnormal differentiation in rat cardiac fibroblasts via the p38MAPK and ERK1/2 signaling pathways.

Abstract

Interstitial fibrosis serves a causal role in the development of heart failure following acute and chronic myocardial infarction, and anti-fibrotic therapy represents a promising strategy to mitigate this pathological process. Oxymatrine (OMT) exerts a number of pharmacological effects on the cardiovascular system, but its anti-cardiovascular disease mechanisms remain unclear. The purpose of the present study was to investigate the effect of OMT administration on transforming growth factor (TGF)-β1-induced cardiac fibroblast (CFB) proliferation and abnormal differentiation, and to elucidate the underlying mechanisms. Primary CFBs were isolated from neonatal rats and used for experimental treatments. TGF-β1 stimulation in CFBs resulted in increased proliferation, increased α-smooth muscle actin (SMA) and type I and type III collagen expression, and increased p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK)1/2 phosphorylation. Treatment with OMT and SB431542 (a TGF-β1 receptor inhibitor) attenuated the proliferation and abnormal differentiation of CFBs induced by TGF-β1, and decreased p38MAPK and ERK1/2 phosphorylation. In addition, treatment with SB203580 (a p38MAPK inhibitor) or PD98059 (an ERK1/2 inhibitor), but not by SP600125 (a c-jun N-terminal kinase1/2/3 inhibitor), inhibited the TGF-β1 stimulated CFB proliferation, as well as the elevation of α-SMA and the deposition of type I and type III collagen, suggesting that ERK1/2 and p38MAPK signaling may be important in the in the process of myocardial fibrosis. In conclusion, the present study revealed that OMT treatment inhibited CFB proliferation and the CFB-myofibroblast transition induced by TGF-β1, at least in part through inhibition of ERK1/2 and p38MAPK signaling.