Hua-Qing Zhu1, Qing li2, Liu-Yi Dong3, Qing Zhou2, Hua Wang4, Yuan Wang2. 1. Laboratory of Molecular Biology and Department of Biochemistry, Anhui Medical University, Hefei, Anhui, People's Republic of China; Key Laboratory of Gene Research of Anhui Province, Hefei, Anhui, People's Republic of China. Electronic address: aydzhq@126.com. 2. Laboratory of Molecular Biology and Department of Biochemistry, Anhui Medical University, Hefei, Anhui, People's Republic of China; Key Laboratory of Gene Research of Anhui Province, Hefei, Anhui, People's Republic of China. 3. Department of Pharmacology, Anhui Medical University, Hefei, Anhui, People's Republic of China. 4. Department of Oncology, The first Affiliated Hospital of Anhui Medical University, Anhui, People's Republic of China. Electronic address: wanghua@ahmu.edu.cn.
Abstract
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 knock-out 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-κB) 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 down-regulation of MT1. Thus, miR-29b may be a new therapeutic target for atherosclerosis.
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 knock-out 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-κB) 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 down-regulation of MT1. Thus, miR-29b may be a new therapeutic target for atherosclerosis.