Abstract
Background and aimsThe CCL20/CCR6 axis has been shown to play a vital role in the pathogenesis of atherosclerosis (AS). However, the regulatory mechanism remains unclear. Here, we studied the miRNA-mediated epigenetic regulation of the CCL20/CCR6 axis in atherogenesis. MethodsCCR6+/+ApoE−/− and CCR6−/−ApoE−/− mice were fed a high-fat diet for 24 weeks. Plaque size was evaluated via ultrasound biomicroscope and hematoxylin and eosin. Protein expression were measured by Western blotting or immunofluorescence/immunohistochemistry or ELISA, and gene mRNA levels were detected by RT-PCR. Seven hundred and sixty miRNAs were screened via miRNA profiling. miRNA-27b target genes were predicted using software and verified with a dual luciferase reporter assay. The tube formation of mouse aortic endothelial cells (MAECs) was performed on Matrigel. ResultsIn contrast to wild-type ApoE−/− mice, CCR6 deficiency led to a significantly decreased plaque size, CD31, CCR6, CCL20 expression and number of CCL20+ macrophages in atherosclerotic plaques. Stimulation of mouse primary peritoneal macrophages (MPPMs) resulted in increased IL-23 release. miRNA-27b was the most highly expressed (5.19-fold increase) miRNA among the 760 miRNAs screened in the vessel. Naa15 was verified as miRNA-27b target gene, which was diminished in the plaques. Transfection of siRNA Naa15 or miRNA-27b mimic into MAECs caused an increase tube formation. ConclusionsCCR6 deletion effectively ameliorates atherosclerosis progression by reducing macrophage accumulation, resulting in reduced secretion of CCL20 and IL-23. Mechanistically, the decreased miRNA-27b regulates the activity of the CCL20/CCR6 axis by targeting Naa15, and promotes plaque stability in atherosclerosis.
Published Version
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