Notoginsenoside R1 inhibits TNF-α-induced fibronectin production in smooth muscle cells via the ROS/ERK pathway

The matrix fibronectin protein plays an important role in vascular remodeling. Notoginsenoside RI is the main ingredient with cardiovascular activity in Panax notoginseng; however, its molecular mechanisms are poorly understood. We report that notoginsenoside RI significantly decreased TNF-alpha-induced activation of fibronectin mRNA, protein levels, and secretion in human arterial smooth muscle cells (HASMCs) in a dose-dependent manner. Notoginsenoside RI scavenged hydrogen peroxide (H2O2) in a dose-dependent manner in the test tube. TNF-alpha significantly increased intracellular ROS generation and then ERK activation, which was blocked by notoginsenoside RI or DPI and apocynin, inhibitors of NADPH oxidase, or the antioxidant NAC. Our data demonstrated that TNF-alpha-induced upregulation of fibronectin mRNA and protein levels occurs via activation of ROS/ERK, which was prevented by treatment with notoginsenoside RI, DPI, apocynin, NAC, or MAPK/ERK inhibitors PD098059 and U0126. Notoginsenoside RI significantly inhibited H2O2-induced upregulation of fibronectin mRNA and protein levels and secretion; it also significantly inhibited TNF-alpha and H2O2-induced migration. These results suggest that notoginsenoside RI inhibits TNF-a-induced ERK activation and subsequent fibronectin overexpression and migration in HASMCs by suppressing NADPH oxidase-mediated ROS generation and directly scavenging ROS. (c) 2006 Elsevier Inc. All rights reserved.