The microRNA-342-5p Fosters Inflammatory Macrophage Activation Through an Akt1- and microRNA-155 –Dependent Pathway During Atherosclerosis

Ovid Technologies (Wolters Kluwer Health) - Tập 127 Số 15 - Trang 1609-1619 - 2013
Yuanyuan Wei1, Maliheh Nazari-Jahantigh1, Lily Chan1, Mengyu Zhu1, Kathrin Heyll1, Judit Corbalán-Campos1, Petra Hartmann1, Anna Thiemann1, Christian Weber1, Andreas Schober1
1From Experimental Vascular Medicine, Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich (Y.W., M.N.-J., M.Z., K.H., J.C.-C., P.H., C.W., A.S.); Institute for Molecular Cardiovascular Research, RWTH Aachen University, Aachen (Y.W., M.-N.J., L.C., K.H., A.T., C.W., A.S.); and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich (C.W., A.S.), Germany.

Tóm tắt

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.

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Ovid Technologies (Wolters Kluwer Health)

Tập 127 Số 15

1609-1619

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