Abstract
Long non‐coding RNAs (lncRNAs) have been indicated for the regulatory roles in cardiovascular diseases. This study determined the expression of lncRNA TNK2 antisense RNA 1 (TNK2‐AS1) in oxidized low‐density lipoprotein (ox‐LDL)‐stimulated human aortic smooth muscle cells (HASMCs) and examined the mechanistic role of TNK2‐AS1 in the proliferation and migration of HASMCs. Our results demonstrated that ox‐LDL promoted HASMC proliferation and migration, and the enhanced proliferation and migration in ox‐LDL‐treated HASMCs were accompanied by the up‐regulation of TNK2‐AS1. In vitro functional studies showed that TNK2‐AS1 knockdown suppressed cell proliferation and migration of ox‐LDL‐stimulated HASMCs, while TNK2‐AS1 overexpression enhanced HASMC proliferation and migration. Additionally, TNK2‐AS1 inversely regulated miR‐150‐5p expression via acting as a competing endogenous RNA (ceRNA), and the enhanced effects of TNK2‐AS1 overexpression on HASMC proliferation and migration were attenuated by miR‐150‐5p overexpression. Moreover, miR‐150‐5p could target the 3’ untranslated regions of vascular endothelial growth factor A (VEGFA) and fibroblast growth factor 1 (FGF1) to regulate FGF1 and VEGFA expression in HASMCs, and the inhibitory effects of miR‐150‐5p overexpression in ox‐LDL‐stimulated HASMCs were attenuated by enforced expression of VEGFA and FGF1. Enforced expression of VEGFA and FGF1 also partially restored the suppressed cell proliferation and migration induced by TNK2‐AS1 knockdown in ox‐LDL‐stimulated HASMCs, while the enhanced effects of TNK2‐AS1 overexpression on HASMC proliferation and migration were attenuated by the knockdown of VEGFA and FGF1. Collectively, our findings showed that TNK2‐AS1 exerted its action in ox‐LDL‐stimulated HASMCs via regulating VEGFA and FGF1 expression by acting as a ceRNA for miR‐150‐5p.
Highlights
Atherosclerosis is a vascular disorder characterized by the accu‐ mulation of fibrous elements and lipids in the vascular wall and is a major cause of cardiovascular disease‐related deaths.[1]
Various studies have demonstrated that hyper‐proliferation and enhanced migration of vascular smooth muscle cells (VSMCs) contributed to the pathogenesis of atherosclerosis,[16] and finding novel targets that repress VSMC pro‐ liferation and migration may represent an effective strategy for al‐ leviating atherosclerosis
We found that oxidized low‐density lipoprotein (ox‐LDL), a well‐documented risk contributor for atherosclerosis,[15] promoted human aortic smooth muscle cells (HASMCs) proliferation and migration, and the enhanced proliferation and migration in ox‐LDL‐treated HASMCs was accompanied by the up‐regulation of TNK2‐AS1
Summary
Atherosclerosis is a vascular disorder characterized by the accu‐ mulation of fibrous elements and lipids in the vascular wall and is a major cause of cardiovascular disease‐related deaths.[1]. The pathophysiology of atherosclerosis remains unclear, and recent evidence pointed to vascular smooth muscle cells (VSMCs) as the key factor in the development of atherosclerosis.[4,5]. Studies showed that abnormal VSMC proliferation, migration and synthesis of extracellular matrix by VSMCs contribute to the formation of the atherosclerotic plaque.[6,7]. In the aspect of atheroscle‐ rosis, lncRNA retinal non‐coding RNA 3 knockdown promoted athero‐ sclerosis by enhancing endothelial cell and VSMC proliferation.[11]. The lncRNA UCA1 was up‐regulated in oxidized low‐density lipoprotein (ox‐LDL)‐stimulated VSMCs and promoted VSMC migration and pro‐ liferation via suppressing miR‐26a expression,[12] which contributed to the development of atherosclerosis. We determined the expression of TNK2‐AS1 in ox‐ LDL‐stimulated human aortic smooth muscle cells (HASMCs) and ex‐ amined the effects of TNK2‐AS1 on the proliferation and migration of HASMCs. the underlying regulatory pathways of TNK2‐AS1 were explored by in vitro assays. The present study may provide us with better understanding regarding the role of ln‐ cRNA in HASMC proliferation and migration
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