Abstract
Background:
Atherosclerosis is a chronic inflammatory vascular disease driven by the subendothelial accumulation of macrophages. The mechanism regulating the inflammatory response in macrophages during atherogenesis remains unclear. Because microRNAs (miRNAs) play a crucial role in cellular signaling by posttranscriptional regulation of gene expression, we studied the miRNA expression profiles during the progression of atherosclerosis.
Methods and results:
Using an miRNA real-time polymerase chain reaction array, we found that macrophage-derived miR-342-5p and miR-155 are selectively upregulated in early atherosclerotic lesions in Apoe(-/-) mice. miR-342-5p directly targets Akt1 through its 3'-untranslated region. Akt1 suppression by miR-342-5p induces proinflammatory mediators such as Nos2 and II6 in macrophages via the upregulation of miR-155. The local application of an miR-342-5p antagomir inhibits the development of atherosclerosis in partially ligated carotid arteries. In atherosclerotic lesions, the miR-342-5p antagomir upregulated Akt1 expression and suppressed the expression of miR-155 and Nos2. This reduced Nos2 expression was associated with a diminished generation of nitrotyrosine in the plaques. Furthermore, systemic treatment with an inhibitor of miR-342-5p reduced the progression of atherosclerosis in the aorta of Apoe(-/-) mice.
Conclusions:
Macrophage-derived miR-342-5p promotes atherosclerosis and enhances the inflammatory stimulation of macrophages by suppressing the Akt1-mediated inhibition of miR-155 expression. Therefore, targeting miR-342-5p may offer a promising strategy to treat atherosclerotic vascular disease.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Aortic Diseases / genetics
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Aortic Diseases / pathology
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Aortic Diseases / physiopathology
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Apolipoproteins E / deficiency
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Atherosclerosis / genetics
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Atherosclerosis / pathology*
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Atherosclerosis / physiopathology
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Bone Morphogenetic Protein Receptors, Type II / biosynthesis
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Bone Morphogenetic Protein Receptors, Type II / genetics
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Carotid Stenosis / genetics
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Carotid Stenosis / pathology
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Carotid Stenosis / physiopathology
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Carotid Stenosis / prevention & control
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Chemokine CCL2 / biosynthesis
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Chemokine CCL2 / genetics
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DEAD-box RNA Helicases / deficiency
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DEAD-box RNA Helicases / genetics
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Disease Progression
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Gene Expression Regulation* / drug effects
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Interleukin-6 / biosynthesis
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Interleukin-6 / genetics
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Macrophage Activation*
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Macrophages / metabolism
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Mice
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Mice, Knockout
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MicroRNAs / antagonists & inhibitors
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MicroRNAs / biosynthesis
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MicroRNAs / genetics
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MicroRNAs / physiology*
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Nitric Oxide Synthase Type II / biosynthesis
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Nitric Oxide Synthase Type II / genetics
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Oligonucleotides / pharmacology
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Oligonucleotides / therapeutic use
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Proto-Oncogene Proteins c-akt / physiology*
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RNA, Antisense / pharmacology
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RNA, Antisense / therapeutic use
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Ribonuclease III / deficiency
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Ribonuclease III / genetics
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Signal Transduction / physiology
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Tyrosine / analogs & derivatives
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Tyrosine / metabolism
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Up-Regulation
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Vasculitis / genetics
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Vasculitis / pathology*
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Vasculitis / physiopathology
Substances
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Apolipoproteins E
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Ccl2 protein, mouse
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Chemokine CCL2
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Interleukin-6
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MicroRNAs
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Mirn155 microRNA, mouse
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Mirn342 microRNA, mouse
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Oligonucleotides
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RNA, Antisense
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locked nucleic acid
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3-nitrotyrosine
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Tyrosine
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Nitric Oxide Synthase Type II
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Nos2 protein, mouse
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Akt1 protein, mouse
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Proto-Oncogene Proteins c-akt
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Bmpr2 protein, mouse
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Bone Morphogenetic Protein Receptors, Type II
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Dicer1 protein, mouse
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Ribonuclease III
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DEAD-box RNA Helicases