Notoginsenoside R1 inhibits vascular smooth muscle cell proliferation, migration and neointimal hyperplasia through PI3K/Akt signaling

Haihong Fang,Renjing Liu,Yi Rao,Cheng Zhang,Yulin Feng,Shilin Yang,Jun Yu,Yingying Luo

doi:10.1038/s41598-018-25874-y

Abstract

Restenosis caused by neointimal hyperplasia significantly decreases long-term efficacy of percutaneous transluminal angioplasty (PTA), stenting, and by-pass surgery for managing coronary and peripheral arterial diseases. A major cause of pathological neointima formation is abnormal vascular smooth muscle cell (VSMC) proliferation and migration. Notoginsenoside R1 (NGR1) is a novel saponin that is derived from Panax notoginseng and has reported cardioprotective, neuroprotective and anti-inflammatory effects. However, its role in modulating VSMC neointima formation remains unexplored. Herein, we report that NGR1 inhibits serum-induced VSMC proliferation and migration by regulating VSMC actin cytoskeleton dynamics. Using a mouse femoral artery endothelium denudation model, we further demonstrate that systemic administration of NGR1 had a potent therapeutic effect in mice, significantly reducing neointimal hyperplasia following acute vessel injury. Mechanistically, we show that NGR1’s mode of action is through inhibiting the activation of phosphatidylinositol 3-kinase (PI3K)/Akt signaling. Taken together, this study identified NGR1 as a potential therapeutic agent for combating restenosis after PTA in cardiovascular diseases.

Highlights

Restenosis as a result of intimal hyperplasia is a major cause of coronary artery and peripheral arterial disease[1,2,3,4]
Notoginsenoside R1 (NGR1) has an effect on neointimal hyperplasia, we performed the mouse femoral artery injury model in C57BL/6J mice injected with vehicle or NGR1
The endothelial layer of the femoral artery is denuded by passaging of a guided wire, and extensive neointima is formed as a result of medial vascular smooth muscle cell (VSMC) proliferation and migration[23,24,25]

Summary

Introduction

Restenosis as a result of intimal hyperplasia is a major cause of coronary artery and peripheral arterial disease[1,2,3,4]. Panax notoginseng saponins (PNS) are the major active ingredients of Panax, with known effects in inhibiting platelet aggregation, promoting cardiac angiogenesis, improving left ventricular diastolic function, is anti-inflammatory, and inhibit vascular intimal hyperplasia and VSMC proliferation[10,11,12,13]. In VSMC, NGR1 reduces the production of fibronectin and plasminogen activator inhibitor-1 (PAI-1) induced by TNF-α via ERK/PKB inhibition[20,22] These findings support a protective role of NGR1 in preventing thrombosis and supporting the endothelium. Our data points to a model wherein NGR1 can potently inhibit serum-induced VSMC proliferation and migration, and attenuate neointima formation in a mouse acute femoral artery injury model through Akt signalling. Our results reveal for the first time that NGR1 is a potential agent for treatment of restenosis after PTA

Methods

Results

Conclusion