MicroRNA-9 overexpression suppresses vulnerable atherosclerotic plaque and enhances vascular remodeling through negative regulation of the p38MAPK pathway via OLR1 in acute coronary syndrome |
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Authors: | Dao-Rui Yu Tao Wang Jing Huang Xing-Yue Fang Hao-Fei Fan Guo-Hui Yi Qiang Liu Yu Zhang Xiang-Zhou Zeng Qi-Bing Liu |
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Institution: | 1. Department of Pharmacology, School of Basic Medicine and Life Science, Hainan Medical University, Haikou, China
Dao-Rui Yu and Tao Wang have contributed equally to this study.;2. Department of nursing humanities, International Nursing School, Hainan Medical University
Dao-Rui Yu and Tao Wang have contributed equally to this study.;3. Department of Pharmacology, School of Basic Medicine and Life Science, Hainan Medical University, Haikou, China;4. Instrument testing center, Public Research Laboratory, Hainan Medical University;5. Department of Pharmacology, School of Pharmacy, Nanjing Medical University |
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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. |
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Keywords: | acute coronary syndrome (ACS) microRNA-9 (miR-9) oxidized low-density lipoprotein (lectin-like) receptor 1 (OLR1) p38-mitogen-activated protein kinase (p38MAPK) pathway vascular remodeling vulnerable atherosclerotic plaque |
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