Bavachin Protects Human Aortic Smooth Muscle Cells Against β-Glycerophosphate-Mediated Vascular Calcification and Apoptosis via Activation of mTOR-Dependent Autophagy and Suppression of β-Catenin Signaling.

Hu-Qiang He,An-Guo Wu,Yan-Zheng He,Cong-Ling Qiu,Vincent Kam Wai Wong,Yong Liu,Yu Han,Ni Zhang,Wen-Lu Zheng,Betty Yuen Kwan Law,Qi Song,Yuan-Qing Qu

doi:10.3389/fphar.2019.01427

Abstract

Vascular calcification is a major complication of cardiovascular disease and chronic renal failure. Autophagy help to maintain a stable internal and external environment that is important for modulating arteriosclerosis, but its pathogenic mechanism is far from clear. Here, we aimed to identify the bioactive compounds from traditional Chinese medicines (TCM) that exhibit an anti-arteriosclerosis effect. In β-glycerophosphate (β-GP)-stimulated human aortic smooth muscle cells (HASMCs), the calcium level was increased and the expression of the calcification-related proteins OPG, OPN, Runx2, and BMP2 were all up-regulated, followed by autophagy induction and apoptosis. Meanwhile, we further revealed that β-GP induced apoptosis of human osteoblasts and promoted differentiation of osteoblasts through Wnt/β-catenin signaling. Bavachin, a natural compound from Psoralea corylifolia, dose-dependently reduced the level of intracellular calcium and the expression of calcification-related proteins OPG, OPN, Runx2 and BMP2, thus inhibiting cell apoptosis. In addition, bavachin increased LC3-II and beclin1 expression, along with intracellular LC3-II puncta formation, which autophagy induction is Atg7-dependent and is regulated by suppression of mTOR signaling. Furthermore, addition of autophagy inhibitor, wortmannin (WM) attenuated the inhibitory effect of bavachin on β-GP-induced calcification and apoptosis in HASMCs. Collectively, the present study revealed that bavachin protects HASMCs against apoptosis and calcification by activation of the Atg7/mTOR-autophagy pathway and suppression of the β-catenin signaling, our findings provide a potential clinical application for bavachin in the therapy of cardiovascular disease.

Highlights

Vascular calcification (VC) is the pathogenic process of accumulating the crystals of calcium phosphate with in the blood vessel (Hofmann Bowman and McNally, 2012; Sun et al, 2012; Yahagi et al, 2017; Chellan et al, 2018; Benjamin et al, 2019)
To determine whether autophagy could be induced by bavachin after β-GP treatment in human aortic smooth muscle cells (HASMCs), we investigated the ratio of LC3-phosphatidylethanolamine conjugate (LC3-II)/β-actin, beclin1, p62, and Phospho mechanistic target of rapamycin (p-mTOR)
We investigated the effect of bavachin on the β-GPinduced apoptosis and calcification in HASMCs

Summary

Introduction

Vascular calcification (VC) is the pathogenic process of accumulating the crystals of calcium phosphate with in the blood vessel (Hofmann Bowman and McNally, 2012; Sun et al, 2012; Yahagi et al, 2017; Chellan et al, 2018; Benjamin et al, 2019). VC has been recognized as a marker of atherosclerotic plaques, which involves a complex pathological process, and has very high morbidity and mortality (Thompson and Towler, 2012; Asmat et al, 2016; Kay et al, 2016). Previous studies have reported that VC is a passive process resulting from the accumulation of calcium phosphate (Thompson and Towler, 2012). VC is resulted from a complex pathophysiological process, comprising several different mechanisms, including hypercalcemia, inflammatory cytokines, oxidative stress, etc. Cai et al (2016) reported that Wnt/β-catenin signaling enhances osteogenic differentiation and calcification of VSMCs by direct up-regulation of Runx

Objectives

Methods

Findings

Conclusion