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

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-derivedmiR-342-5p andmiR-155 are selectively upregulated in early atherosclerotic lesions inApoe −/− mice.miR-342-5p directly targetsAkt1 through its 3′-untranslated region.Akt1 suppression bymiR-342-5p induces proinflammatory mediators such asNos2 andII6 in macrophages via the upregulation ofmiR-155 . The local application of anmiR-342-5p antagomir inhibits the development of atherosclerosis in partially ligated carotid arteries. In atherosclerotic lesions, themiR-342-5p antagomir upregulatedAkt1 expression and suppressed the expression ofmiR-155 andNos2 . This reducedNos2 expression was associated with a diminished generation of nitrotyrosine in the plaques. Furthermore, systemic treatment with an inhibitor ofmiR-342-5p reduced the progression of atherosclerosis in the aorta ofApoe −/− mice.Conclusions— Macrophage-derivedmiR-342-5p promotes atherosclerosis and enhances the inflammatory stimulation of macrophages by suppressing theAkt1 -mediated inhibition ofmiR-155 expression. Therefore, targetingmiR-342-5p may offer a promising strategy to treat atherosclerotic vascular disease.