Objective. Icariin plays a pivotal role in ameliorating atherosclerosis for animal models although its comprehensive biological role remains largely unexplored. This study aimed to fully understand the effects of icariin on atherosclerosis in high-fat diet-induced ApoE-/- mice and investigate mRNA-miRNA regulation based on microarray and bioinformatics analysis. Methods. The areas of atherosclerotic lesions in en face aorta were evaluated. Microarray analysis was performed on atherosclerotic

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... tic tissues. The integrative analysis of mRNA and miRNA profiling was utilized to suggest specific functions of gene and supply an integrated and corresponding method to study the protective effect of icariin on atherosclerosis. Results. Icariin attenuated the development of atherosclerosis that the mean atherosclerotic lesion area was reduced by 5.8% (P < 0.05). Significant changes were observed in mRNA and miRNA expression patterns. Several miRNAs obtained from the miRNA-Gene-Network might play paramount part in antiatherosclerotic effect of icariin, such as mmu-miR-6931-5p, mmu-miR-3547-5p, mmu-miR-5107-5p, mmu-miR-6368, and mmu-miR-7118-5p. Specific miRNAs and GO terms associated with icariin in the pathogenesis of atherosclerosis were validated using GO analysis and miRNA-GO-Network. MiRNA-Pathway-Network indicated that icariin induced miRNAs mainly regulate the signaling pathways of PI3K/Akt signaling pathway, Ras signaling pathway, ErbB signaling pathway, and VEGF signaling pathway in aorta atherosclerotic lesion. Conclusions. Our data provides evidence that icariin is able to exhibit one antiatherosclerotic action by mediating multiple biological processes or cascades, suggesting the pleiotropic effects of icariin in atherosclerosis alleviation. The identified gene functional categories and pathways are potentially valuable targets for future development of RNA-guided gene regulation to fight disease.