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. As 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 PCR array, we found that macrophage-derived miR-342-5p and miR-155 are selectively up-regulated in early atherosclerotic lesions in Apoe-/- mice. miR-342-5p directly targets Akt1 through its 3'UTR. Akt1 suppression by miR-342-5p induces proinflammatory mediators, such as Nos2 and II6 in macrophages, via the up-regulation 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 up-regulated 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 reduces 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.
- Received December 18, 2012.
- Revision received February 27, 2013.
- Accepted March 8, 2013.