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  • Title: Apolipoprotein E enhances microRNA-146a in monocytes and macrophages to suppress nuclear factor-κB-driven inflammation and atherosclerosis.
    Author: Li K, Ching D, Luk FS, Raffai RL.
    Journal: Circ Res; 2015 Jun 19; 117(1):e1-e11. PubMed ID: 25904598.
    Abstract:
    RATIONALE: Apolipoprotein E (apoE) exerts anti-inflammatory properties that protect against atherosclerosis and other inflammatory diseases. However, mechanisms by which apoE suppresses the cellular activation of leukocytes commonly associated with atherosclerosis remain incompletely understood. OBJECTIVE: To test the hypothesis that apoE suppresses inflammation and atherosclerosis by regulating cellular microRNA levels in these leukocytes. METHODS AND RESULTS: An assessment of apoE expression among such leukocyte subsets in wild-type mice revealed that only macrophages and monocytes express apoE abundantly. An absence of apoE expression in macrophages and monocytes resulted in enhanced nuclear factor-κB signaling and an exaggerated inflammatory response on stimulation with lipopolysaccharide. This correlated with reduced levels of microRNA-146a, a critical negative regulator of nuclear factor-κB signaling. Ectopic apoE expression in Apoe(-/-) macrophages and monocytes raised miR-146a levels, whereas its silencing in wild-type cells had an opposite effect. Mechanistically, apoE increased the expression of transcription factor purine-rich PU-box-binding protein 1, which raised levels of pri-miR-146 transcripts, demonstrating that apoE exerts transcriptional control over miR-146a. In vivo, even a small amount of apoE expression in macrophages and monocytes of hypomorphic apoE mice led to increased miR-146a levels, and inhibited macrophage proinflammatory responses, Ly-6C(high) monocytosis, and atherosclerosis in the settings of hyperlipidemia. Accordingly, cellular enrichment of miR-146a through the systemic delivery of miR-146a mimetics in Apoe(-/-)Ldlr(-/-) and Ldlr(-/-) mice attenuated monocyte/macrophage activation and atherosclerosis in the absence of plasma lipid reduction. CONCLUSIONS: Our data demonstrate that cellular apoE expression suppresses nuclear factor-κB-mediated inflammation and atherosclerosis by enhancing miR-146a levels in monocytes and macrophages.
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