MicroRNA-29b promotes high-fat diet-stimulated endothelial permeability and apoptosis in apoE knock-out mice by down-regulating MT1 expression

Background: High-fat diet has been reported to be associated with cardiovascular diseases which is implicated in atherosclerosis. However, the underlying mechanisms remain unknown. MicroRNAs (miRNAs) are non-coding small RNAs that control gene expression at the post-transcriptional level. Dysregulated miRNAs have been shown to be involved in atherosclerosis. Methods and results: This study examined whether microRNA-29b (miR-29b) regulates high-fat diet induced endothelial permeability and apoptosis by targeting MT1, a known melatonin membrane receptor. In apoE knockout mice, a high-fat diet increased miR-29b expression and induced apoptosis as determined by up-regulation of caspase-3 activity. However, a standard diet did not alter apoptosis. miR-29b antagomir decreased endothelial permeability and apoptosis in high-fat diet-stimulated mice. In contrast, a miR-29b mimic enhanced endothelial permeability and apoptosis. The induction of miR-29b correlated with a reduction in Bcl-2 and MT1 in high-fat diet-stimulated mice. miR-29b have an effect on the marker of inflammation (NF-kappa B) and cell adhesion molecule (ICAM-1). We further showed that miR-29b targeted and inhibited MT1 expression through a target site located in the 3' un-translational region of MT1 mRNA. This study demonstrates a role of miR-29b in atherosclerosis and identifies MT1 as a direct target of miR-29b. Conclusions: The effect of miR-29b on endothelial permeability and apoptosis is mediated through the downregulation of MT1. Thus, miR-29b may be a new therapeutic target for atherosclerosis. (C) 2014 Elsevier Ireland Ltd. All rights reserved.