MicroRNA‐9 overexpression suppresses vulnerable atherosclerotic plaque and enhances vascular remodeling through negative regulation of the p38MAPK pathway via OLR1 in acute coronary syndrome

Abstract

Acute coronary syndrome (ACS) is characterized by atherosclerotic plaque rupture with a high incidence of recurrent ischemic events. Several microRNAs are found to be aberrantly expressed in atherosclerotic plaques. This study aims to investigate the effects of microRNA‐9 (miR‐9) on vulnerable atherosclerotic plaque and vascular remodeling in ACS and underlying mechanisms. Microarray‐based gene expression profiling was used to identify differentially expressed genes related to ACS and regulatory miRNAs. Oxidized low‐density lipoprotein (lectin‐like) receptor 1 (OLR1) was identified to be aberrantly activated in ACS and regulated by miR‐9. OLR1 was verified as a target gene of miR‐9 by bioinformatics prediction and dual luciferase reporter gene assay. The atherosclerotic models were induced in ApoE−/− mice, in which the agomir or antagomir of miR‐9, or small interfering RNA (siRNA) against OLR1 were separately introduced. Serum lipid levels and expression of vascular remodeling and inflammatory response‐related factors were determined, respectively. On the basis of the obtained results, in the atherosclerosis mice treated with the agomir of miR‐9 and siRNA against OLR1, the p38‐mitogen‐activated protein kinase (p38MAPK) pathway was inhibited; levels of triglyceride, total cholesterol, low‐density lipoprotein cholesterol, tumor necrosis factor‐α, interleukin‐6, and vascular endothelial growth factor were reduced, but the high‐density lipoprotein cholesterol level was increased, along with decreased vulnerable atherosclerotic plaque area and enhanced vascular remodeling. Taken together, these findings suggested an inhibitory role miR‐9 acts in the formation of vulnerable atherosclerotic plaques in ACS mice, along with a promoted vascular remodeling, via a negative feedback regulation of OLR1‐mediated p38MAPK pathway.

microRNA-9 Inhibits Vulnerable Plaque Formation and Vascular Remodeling via Suppression of the SDC2-Dependent FAK/ERK Signaling Pathway in Mice With Atherosclerosis

“…A recent study has reported that the over-expression of miR-150 maintains the function of endothelial cells and suppresses VR by inhibiting pentraxin-3 (PTX3) expression, as well as activation of the NF-κB signaling pathway in ACS mice ( Luo et al, 2018 ). Moreover, up-regulated miR-9 is known to suppress the formation of vulnerable atherosclerotic plaques and enhance VR in ACS mice through negative-regulation of the p38MAPK pathway via OLR1, while our findings indicate a similar function via inhibition of the FAK/ERK signaling pathway ( Yu et al, 2020 ). Over-expression of miR-9 in bone marrow-derived mesenchymal stem cells is also known to diminish the levels of IL-6, IL-1β, and TNF-α in acute pancreatitis, highlighting the critical role of miR-9 up-regulation in inhibition of inflammatory responses ( Qian et al, 2017 ).…”

“…Moreover, significantly diminished expression of miRNAs such as miR-17, miR-126, and miR-155, has been previously documented in patients with coronary artery disease ( Izawa and Amano, 2015 ). Besides that, Yu et al (2020) observed poor miR-9 expression in n the aortic tissue of mice with atherosclerosis. miRNAs possess the ability to modulate gene expression post-transcriptionally by comprehensively interacting with the 3’UTR of specific target mRNAs ( Ivey and Srivastava, 2015 ).…”

“…The HFD mice were then treated with short hairpin RNA-negative control (sh-NC) vector, sh-SDC2, agomir NC, and miR-9 agomir. The miR-9 agomir or agomir NC was dissolved in 0.2 mL normal saline and injected into the mice at a dose of 80 mg/kg/d via the tail vein once a day for ten consecutive days ( Yu et al, 2020 ). Lentivirus carrying oe-SDC2 or sh-SDC2 was then injected into the mice at a dose of 1 × 10 7 PFU/mouse via the tail vein, once every 2 days.…”

Enhancer of zeste homolog 2 participates in the process of atherosclerosis by modulating microRNA‐139‐5p methylation and signal transducer and activator of transcription 1 expression

“…8 In addition, another study suggests miR-9 suppresses vulnerable atherosclerotic plaque in acute coronary syndrome mice. 9 microRNA-139-5p (miR-139-5p) has been previously known as being aberrant regulated in some cardiac ischemia/reperfusion models. 10 miR-139-5p has also been reported to restrain isoproterenol-induced cardiac hypertrophy.…”

“…For example, a study indicates that up‐regulated miR‐377 partly relieves the progress of AS 8 . In addition, another study suggests miR‐9 suppresses vulnerable atherosclerotic plaque in acute coronary syndrome mice 9 . microRNA‐139‐5p (miR‐139‐5p) has been previously known as being aberrant regulated in some cardiac ischemia/reperfusion models 10 .…”