Ganoderma triterpenes Protect Against Hyperhomocysteinemia Induced Endothelial-Mesenchymal Transition via TGF-β Signaling Inhibition.

Jinzhao He,Ruoyun Chen,Yingli Jia,Hong Zhou,Xiaoqiang Geng,Yi Sun,Baoxue Yang

doi:10.3389/fphys.2019.00192

Abstract

Endothelial dysfunction is one of the most important pathological status in hyperhomocysteinemia (HHcy) related cardiovascular diseases. Whereas, the underlying mechanisms have not been fully elucidated yet, concomitant with the absence of effective treatment. The purpose of this study was to explore the main mechanisms involved in HHcy-induced endothelial injury and identify the protective effect of Ganoderma triterpenes (GT). Bovine aortic endothelial cells (BAECs) were applied as in vitro experimental model. The small molecular inhibitors were used to explore the signalings involved in HHcy-induced endothelial injury. The experimental results provided initial evidence that HHcy led to endothelial-mesenchymal transition (EndMT). Meanwhile, TGF-β/Smad, PI3K/AKT and MAPK pathways were activated in this process, which was demonstrated by pretreatment with TGF-β RI kinase inhibitor VI SB431542, PI3K inhibitor LY294002, p38 inhibitor SB203580, and ERK inhibitor PD98059. Furthermore, it was found that GT restrained the process of HHcy-induced EndMT via reducing oxidative stress and suppressing fore mentioned pathways with further inhibiting the activity of Snail. These results implicate that there is an untapped potential for GT as a novel therapeutic candidate for HHcy-induced EndMT through alleviating oxidative stress and canonical TGF-β/Smad and non-Smad dependent signaling pathways.

Highlights

Cardiovascular diseases (CVDs) have severely threatened human health in light of high morbidity and mortality
We provide evidence that endothelialmesenchymal transition (EndMT) is involved in the process of HHcy-induced endothelial injury, which could be alleviated by Ganoderma triterpenes (GT) treatment via reducing oxidative stress and curtailing canonical TGF-β/Smad and nonSmad dependent signalings to regulate Smad and Snail-mediated gene transcription
We found that Bovine aortic endothelial cells (BAECs) lost their cobblestone appearance and presented elongated and spindlelike morphology after stimulating with 800 μM Hcy over 48 h compared with untreated cells (Figure 1A, left panel)

Summary

Introduction

Cardiovascular diseases (CVDs) have severely threatened human health in light of high morbidity and mortality. Hyperhomocysteinemia (HHcy) has been considered as an established independent risk factor for CVDs, such as hypertension, atherosclerosis, heart failure, and stroke (Pushpakumar et al, 2013; Spence et al, 2017). The pathophysiology of HHcy-mediated CVDs is characterized by vascular remodeling, lipid metabolism disorder and endothelial dysfunction (Steed and Tyagi, 2011; Lai and Kan, 2015). HHcy-induced endothelial dysfunction is mainly involved in oxidative stress, inflammation, endoplasmic reticulum (ER) stress, and apoptosis (Lai and Kan, 2015; Wu et al, 2015). Blockage of EndMT through inhibiting the process of oxidative stress has been considered as a promising way to protect from endothelial injury

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