Long non-coding RNA SNHG16 regulates human aortic smooth muscle cell proliferation and migration via sponging miR-205 and modulating Smad2.

Yongqing Lin,Guoping Tian,Yong Xie,Ying Liang,Ying Yang,Jingfeng Wang,Woliang Yuan,Haifeng Zhang

doi:10.1111/jcmm.14576

Abstract

The present study investigated the role of long non‐coding RNA (lncRNA) small nucleolar RNA host gene 16 (SNHG16) in the human aortic smooth muscle cell (HASMC) proliferation and migration and explored the potential link between SNHG16 and atherosclerosis. Our results showed that platelet‐derived growth factor (PDGF)‐bb treatment promoted cell proliferation and migration with concurrent up‐regulation of SNHG16 in HASMCs. Small nucleolar RNA host gene 16 overexpression promoted HASMC proliferation and migration, while SNHG16 knockdown suppressed cell proliferation and migration in PDGF‐bb‐stimulated HASMCs. The bioinformatic analyses showed that SNHG16 possessed the complementary binding sequence with miR‐205, where the interaction was confirmed by luciferase reporter assay and RNA pull‐down assay in HASMCs, and SNHG16 inversely regulated miR‐205 expression. MiR‐205 overexpression attenuated the enhanced effects of PDGF‐bb treatment on HASMC proliferation and migration. Moreover, Smad2 was targeted and inversely regulated by miR‐205, while being positively regulated by SNHG16 in HASMCs. Smad2 knockdown attenuated PDGF‐bb‐mediated actions on HASMC proliferation and migration. Both miR‐205 overexpression and Smad2 knockdown partially reversed the effects of SNHG16 overexpression on HASMC proliferation and migration. Moreover, SNHG16 and Smad2 mRNA were up‐regulated, while miR‐205 was down‐regulated in the plasma from patients with atherosclerosis. Small nucleolar RNA host gene 16 expression was inversely correlated with miR‐205 expression and positively correlated with Smad2 expression in the plasma from atherosclerotic patients. In conclusion, our data showed the up‐regulation of SNHG16 in pathogenic‐stimulated HASMCs and clinical samples from atherosclerotic patients. Small nucleolar RNA host gene 16 regulated HASMC proliferation and migration possibly via regulating Smad2 expression by acting as a competing endogenous RNA for miR‐205.

Highlights

Cardiovascular diseases (CVDs) such as atherosclerosis are the leading cause of death globally.[1,2] The aberrant proliferation of vas‐ cular smooth muscle cells (VSMCs) plays the essential role in the pathogenesis of CVDs such as the development of atherosclerotic plaque.[3,4] Platelet‐derived growth factor (PDGF) exists as three iso‐ forms including PDGF‐aa, PDGF‐ab and PDGF‐bb.[5,6] Studies have found that PDGF‐bb is overexpressed in the VSMCs in the athero‐ sclerotic regions, and PDGF‐bb inhibition reduces the size of ath‐ erosclerotic lesion.[7]
In vitro mechanistic studies demonstrated that PDGF‐bb exerted enhanced effects on the VSMC proliferation and migration, and promoted the extracellular matrix protein secre‐ tion of VSMCs,[8] which may lead to the formation of atherosclerotic plaque
The pathogenesis of atherosclerosis involves both genetic and envi‐ ronmental factors, and the abnormal cellular behaviours of VSMCs are believed to be the main contributor to the development of ath‐ erosclerosis.[4]

Summary

| INTRODUCTION

Cardiovascular diseases (CVDs) such as atherosclerosis are the leading cause of death globally.[1,2] The aberrant proliferation of vas‐ cular smooth muscle cells (VSMCs) plays the essential role in the pathogenesis of CVDs such as the development of atherosclerotic plaque.[3,4] Platelet‐derived growth factor (PDGF) exists as three iso‐ forms including PDGF‐aa, PDGF‐ab and PDGF‐bb.[5,6] Studies have found that PDGF‐bb is overexpressed in the VSMCs in the athero‐ sclerotic regions, and PDGF‐bb inhibition reduces the size of ath‐ erosclerotic lesion.[7]. The aberrant proliferation of vas‐ cular smooth muscle cells (VSMCs) plays the essential role in the pathogenesis of CVDs such as the development of atherosclerotic plaque.[3,4]. In vitro mechanistic studies demonstrated that PDGF‐bb exerted enhanced effects on the VSMC proliferation and migration, and promoted the extracellular matrix protein secre‐ tion of VSMCs,[8] which may lead to the formation of atherosclerotic plaque. In terms of mechanistic actions of ln‐ cRNAs, lncRNAs can function as the competing endogenous RNAs (ceRNAs) for miRNAs, which in turn suppress the expression of targeted miRNAs. For example, lncRNA urothelial cancer associ‐ ated 1 acts as ceRNA for miR‐26a to regulate VSMC proliferation and migration.[21]. We determined the expression of SNHG16 in human aortic smooth muscle cells (HASMCs) under the condition of PDGF‐bb and explored the mechanistic role of SNHG16 in reg‐ ulating HASMC proliferation and migration. Our data from this study may provide us with the advanced understanding of the molecular mechanisms of aberrant HASMC proliferation and migration

| MATERIALS AND METHODS

| DISCUSSION