Downregulation of NAGLU in VEC Increases Abnormal Accumulation of Lysosomes and Represents a Predictive Biomarker in Early Atherosclerosis.

Changchang Xing,Yi Wang,Zhongyi Jiang

doi:10.3389/fcell.2021.797047

Abstract

Cardiovascular diseases (CVDs), predominantly caused by atherosclerosis (AS), are the leading cause of mortality worldwide. Although a great number of previous studies have attempted to reveal the molecular mechanism of AS, the underlying mechanism has not been fully elucidated. The aberrant expression profiling of vascular endothelial cells (VECs) gene in early atherosclerosis (EAS) was analyzed according to the dataset (GSE132651) downloaded from the Gene Expression Omnibus (GEO) database. We primarily performed functional annotation analysis on the downregulated genes (DRGs). We further identified that α-N-acetylglucosaminidase (NAGLU), one of the DRGs, played a critical role in the progression of EAS. NAGLU is a key enzyme for the degradation of heparan sulfate (HS), and its deficiency could cause lysosomal accumulation and lead to dysfunctions of VECs. We found that siRNA knockdown of NAGLU in human umbilical vein endothelial cell (HUVEC) aggravated the abnormal accumulation of lysosomes and HS. In addition, the expression of NAGLU was reduced in the EAS model constructed by ApoE −/- mice. Furthermore, we also showed that heparin-binding EGF-like growth factor (HB-EGF) protein was upregulated while NAGLU knockdown in HUVEC could specifically bind to vascular endothelial growth factor receptor 2 (VEGFR2) and promote its phosphorylation, ultimately activating the phosphorylation levels of extracellular signal-regulated kinases (ERKs). However, the application of selective VEGFR2 and ERKs inhibitors, SU5614 and PD98059, respectively, could reverse the abnormal lysosomal storage caused by NAGLU knockdown. These results indicated that downregulation of NAGLU in HUVEC increases the abnormal accumulation of lysosomes and may be a potential biomarker for the diagnosis of EAS.

Highlights

Cardiovascular diseases (CVDs), predominantly caused by atherosclerosis (AS), are the leading cause of morbidity and mortality worldwide (Herrington et al, 2016)
According to the results of the Pearson’s correlation test (PCT), we showed that there was a strong correlation between the respective samples of the normal endothelial function groups (NG) or abnormal endothelial function groups (ANG) in the GSE132651 dataset (Figure 1B)
It is worth noting that endothelial cell dysfunction (ECD) in arterial vasculature lesions is the earliest detectable change in a variety of pathological processes leading to atherosclerotic lesions (Stary, 2000; Virmani et al, 2000)

Summary

Introduction

Cardiovascular diseases (CVDs), predominantly caused by atherosclerosis (AS), are the leading cause of morbidity and mortality worldwide (Herrington et al, 2016). Previous research has shown that dysfunction of VECs (e.g., endothelial cell activation) that line the arterial vasculature is an important contributor to the pathobiology of AS (Gimbrone and GarcíaCardeña, 2016), which is the earliest detectable change in the progression of AS (Stary, 2000; Virmani et al, 2000). Dysfunction of VECs can induce these cells to produce and secrete cytokines and chemokines, leading to monocyte/lymphocyte recruitment and infiltration into the subendothelium (Hansson, 2005), which further aggravates the progression of AS plaque formation (Tedgui and Mallat, 2006; Bosisio et al, 2014; Paramel Varghese et al, 2016).

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Conclusion