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MicroRNAs (miRs) have been shown to participate in the regulation of atherogenesis. We observed a decrease in plasma levels of miR-98 and an increase in circulating levels of lectin-like ox-low density lipoprotein receptor-1 (sLOX-1) in patients with carotid atherosclerosis, which led us to the hypothesis of this study: miR-98 may influence atherogenesis by modulation of LOX-1.
Plasma samples from 50 patients with carotid atherosclerosis and 50 control subjects were analyzed to detect miRs directed at determinants of atherosclerosis. We assessed the effects of miR-98 on the expression of LOX-1, reactive oxygen species (ROS) production and downstream signaling and its effect on atherogenesis in ApoE-/- mice. Lastly, LOX-1 was established to be a direct target of miR-98 by luciferase reporter assay.
miR-98 was the most downregulated miR in association with an increase in sLOX-1 in patients with atherosclerosis (P<0.05 vs. Control subjects). Enhancement of miR-98 in primary aortic endothelial cells decreased the expression of LOX-1, reduced ROS generation, activation of the redox-sensitive transcription factor NF-kB p65 and expression of ET-1, and upregulated the expression of eNOS. Enhancement of miR-98 also inhibited foam cell formation in macrophages (all P<0.05 vs. Control). Reduction of miR-98, on the other hand, had the opposite effects. Administration of agomiR-98 to the ApoE-/- mice fed high fat diet reduced lipid accumulation (extent of atherosclerosis) in association with reduced expression of LOX-1, phos-NF-kB p65 and ET-1 and increased expression of eNOS (all P<0.05 vs. mice given scrambled miR). Administration of antagomiR-98 had the opposite effects on these parameters.
Reduced expression of miR-98 may relate to excess LOX-1 expression and downstream signaling, foam cell formation and lipid accumulation. Plasma level of miR-98 may be a biomarker of atherosclerotic disease process and its modulation may offer a therapeutic strategy for atherosclerosis.