miR-18a-5p Promotes Proliferation and Migration of Vascular Smooth Muscle Cells by Activating the AKT/Extracellular Regulated Protein Kinases (ERK) Signaling Pathway

Abstract

Background microRNAs (miRNAs) play important roles in abnormal proliferation and migration of vascular smooth muscle cells (VSMCs), which lead to restenosis in coronary artery disease. Nevertheless, the role of miR-18a-5p and how it works in VSMCs remain unknown. Material/Methods miR-18a-5p expression was determined by fluorescence quantitative real-time polymerase chain reaction (qRT-PCR) analysis of tissues from 20 patients with stent restenosis, and rats with carotid artery injury, as well as VSMCs. A cell viability assay was used to measure cell proliferation. Cell migration abilities were assessed by transwell migration assay and wound healing assays. To identify miR-18a-5p targets, a dual-luciferase reporter assay was performed. Western blot analysis and immunofluorescence techniques were used to assess the protein expression levels of AKT and ERK. The rescue effects of miR-18a-5p on the proliferation or migration of VSMCs were evaluated after exposure to the AKT inhibitor MK-2206 and ERK inhibitor PD98059. Results The expression level of miR-18a-5p was significantly higher in the blood serum of patients with stent restenosis and in rats with carotid artery injury, and the expression of AKT and ERK was higher after carotid artery injury. The proliferation and migration abilities of VSMCs were accelerated by the overexpression of miR-18a-5p. It was found that miR-18a-5p directly modulates AKT/ERK signaling. Upregulated miR-18a-5p increased the protein expression levels of AKT and ERK and we found a positive correlation between miR-18a-5p expression level and expression of AKT and ERK. Additionally, the promoting effect of miR-18a-5p on VSMCs proliferation, migration, and invasion was reversed by ERK inhibitor or AKT inhibitor. Conclusions miR-18a-5p can promote proliferation of VSMCs by activating the AKT/ERK signaling pathway.

Upregulated miR-18a-5p in Colony Forming Unit-Hill’s in Subclinical Cardiovascular Disease and Metformin Therapy; MERIT Study

“…We have shown for the first time that miR-18a-5p in CFU-Hill’s colonies is upregulated in T1DM. MiRNA-18a-5p has been suggested to serve an important role in various biological activities leading to the pathogenesis of vascular diseases, as significantly upregulated miRNA-18a-5p was previously reported in the serum of patients with stent stenosis and in animal models with carotid artery injury [ 26 ].…”

“…Accumulating evidence has suggested that the dysregulation of multiple miRNAs is responsible for the pathogenesis of CVD. The overexpression of miRNA-18a-5p has been identified as pro-atherogenic miRNA as it promotes proliferation and migration of vascular smooth muscle cells [ 25 , 26 ]; moreover, an animal model of oxygen-induced proliferative retinopathy revealed that the overexpression of miR-18a-5p in human retinal microvascular endothelial cell, was anti-angiogenic as inhibited angiogenesis via significant downregulation of fibroblast growth factor-1 and hypoxia-inducible factor-1 alpha (HIF-1α), which are both closely associated with angiogenesis [ 27 ]. The anti-angiogenic property of miR-18a-5p renders it an ideal candidate for studying the paracrine function of CFU-Hill’s colonies.…”

Activation of the GTPase ARF6 regulates Invasion of Human Vascular Smooth Muscle Cells by Stimulating MMP14 Activity

“…To better define the molecular mechanisms by which this ARF isoform controls HASMC invasive capabilities, we aimed to identify the different downstream signaling events. In previous studies, PDGF-BB was shown to activate mitogenic cascades, which have been previously associated with VSMC invasion [17][18][19][20] . Here, we therefore first examined whether invasion was modulated by activation of the ERK1/2 pathway.…”

Differential Expression of miRNA-223 in Coronary In-Stent Restenosis

“…It has been reported that both miRNAs [36] and lipoproteins such as HDL [37] could regulate many of the key processes involved in atherosclerosis [38]. Thus, the association between the expression of miRNAs related to the PBMCs [39], VSMCs [40][41][42][43], and vascular endothelial cells [44][45][46] with cardiovascular disease (CVD) and restenosis has been previously discussed [26,39,44]. However, to the best of our knowledge, there is no study that showed the serum expression level of miRNAs related to lipoproteins and lipid metabolism in ISR patients.…”