Long Non-coding RNA H19 Suppression Protects the Endothelium Against Hyperglycemic-Induced Inflammation via Inhibiting Expression of miR-29b Target Gene Vascular Endothelial Growth Factor a Through Activation of the Protein Kinase B/Endothelial Nitric Oxide Synthase Pathway.

Xiao-Wen Cheng,Hua Wang,Zhen-Fei Chen,Yu-Feng Wan,Hua-Qing Zhu,Qing Zhou

doi:10.3389/fcell.2019.00263

Abstract

It has been shown that non-coding RNAs (ncRNAs) play an important regulatory role in pathophysiological processes involving inflammation. The vascular endothelial growth factor A (VEGFA) gene also participates in the inflammatory process. However, the relationships between ncRNAs and VEGFA are currently unclear. Here, this study was designed to determine the relationship between long non-coding RNA (lncRNA) H19, mircoRNA29b (miR-29b), and VEGFA in the development of diabetes mellitus (DM). We demonstrate that H19 is upregulated and miR-29b downregulated in individuals with DM and directly binds miR-29b. VEGFA is the target of miR-29b in the vascular endothelium of individuals with DM. We found that positive modulation of miR29b and inhibition of H19 and VEGFA significantly attenuates high glucose-induced endothelial inflammation and oxidative stress. We also found that the protein kinase B/endothelial nitric oxide synthase (AKT/eNOS) signal pathway in endothelial cells is activated through regulation of miR29b and H19 endogenous RNAs. We conclude that H19 suppression protects the endothelium against high glucose-induced inflammation and oxidative stress in endothelial cells by upregulation of miR-29b and downregulation of VEGFA through AKT/eNOS signal pathway activation. These results suggest a novel link between dysregulated ncRNA expression, inflammation, and the signaling pathway in the vascular endothelium of individuals with DM, indicating a promising strategy for preventing cardiovascular disease in such individuals.

Highlights

Impaired vascular remodeling is considered to be involved in the development of cardiovascular disease (CVD) (GarcíaRedondo et al, 2016)
We explored the interaction between vascular epithelial growth factor A (VEGFA) and H19 during hyperglycemia-induced inflammation and investigated whether miR-29b is involved in this interaction
We surmised that regulating vascular inflammation by regulating expression of inflammationrelated genes may be a means of preventing and treating CVDs

Summary

Introduction

Impaired vascular remodeling is considered to be involved in the development of cardiovascular disease (CVD) (GarcíaRedondo et al, 2016). It is generally accepted that there is a relationship between CVD and vascular inflammation (Haybar et al, 2019). Vascular inflammation contributes to the progression of more complex diseases such as atherosclerosis (AS) and diabetes mellitus (DM). Brownlee (2001) have proposed that hyperglycemia plays a role in promoting overproduction of reactive oxygen species (ROS) by the mitochondrial electron transport chain and that prolonged production of mitochondrial superoxide contributes to development of diabetes-related vascular damage. We aimed to investigate whether vascular epithelial growth factor A (VEGFA), a member of the VEGF family that is considered to be proinflammatory cytokines, is involved in the pathogenesis of CVD in individuals with DM

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