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      An Agomir of miR-144-3p Accelerates Plaque Formation through Impairing Reverse Cholesterol Transport and Promoting Pro-Inflammatory Cytokine Production

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          Abstract

          Aims

          ATP-binding cassette transporter A1 (ABCA1) mediates the efflux of cholesterol and phospholipids to lipid-poor apolipoproteins, which then form nascent HDL, a key step in the mechanism of reverse cholesterol transport (RCT). While a series of microRNAs (miRNAs) have been identified as potent post-transcriptional regulators of lipid metabolism, their effects on ABCA1 function and associated mechanisms remain unclear.

          Methods and Results

          ABCA1 was identified as a potential target of miR-144-3p, based on the results of bioinformatic analysis and the luciferase reporter assay, and downregulated after transfection of cells with miR-144-3p mimics, as observed with real-time PCR and western blot. Moreover, miR-144-3p mimics (agomir) enhanced the expression of inflammatory factors, including IL-1β, IL-6 and TNF-α, in vivo and in vitro, inhibited cholesterol efflux in THP-1 macrophage-derived foam cells, decreased HDL-C circulation and impaired RCT in vivo, resulting in accelerated pathological progression of atherosclerosis in apoE −/− mice. Clinical studies additionally revealed a positive correlation of circulating miR-144-3p with serum CK, CK-MB, LDH and AST in subjects with AMI.

          Conclusions

          Our findings clearly indicate that miR-144-3p is essential for the regulation of cholesterol homeostasis and inflammatory reactions, supporting its utility as a potential therapeutic target of atherosclerosis and a promising diagnostic biomarker of AMI.

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          Most cited references38

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          Lessons From Sudden Coronary Death

          Arteriosclerosis, Thrombosis, and Vascular Biology, 20(5), 1262-1275
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            MiR-33 contributes to the regulation of cholesterol homeostasis.

            Cholesterol metabolism is tightly regulated at the cellular level. Here we show that miR-33, an intronic microRNA (miRNA) located within the gene encoding sterol-regulatory element-binding factor-2 (SREBF-2), a transcriptional regulator of cholesterol synthesis, modulates the expression of genes involved in cellular cholesterol transport. In mouse and human cells, miR-33 inhibits the expression of the adenosine triphosphate-binding cassette (ABC) transporter, ABCA1, thereby attenuating cholesterol efflux to apolipoprotein A1. In mouse macrophages, miR-33 also targets ABCG1, reducing cholesterol efflux to nascent high-density lipoprotein (HDL). Lentiviral delivery of miR-33 to mice represses ABCA1 expression in the liver, reducing circulating HDL levels. Conversely, silencing of miR-33 in vivo increases hepatic expression of ABCA1 and plasma HDL levels. Thus, miR-33 appears to regulate both HDL biogenesis in the liver and cellular cholesterol efflux.
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              MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis.

              Proper coordination of cholesterol biosynthesis and trafficking is essential to human health. The sterol regulatory element-binding proteins (SREBPs) are key transcription regulators of genes involved in cholesterol biosynthesis and uptake. We show here that microRNAs (miR-33a/b) embedded within introns of the SREBP genes target the adenosine triphosphate-binding cassette transporter A1 (ABCA1), an important regulator of high-density lipoprotein (HDL) synthesis and reverse cholesterol transport, for posttranscriptional repression. Antisense inhibition of miR-33 in mouse and human cell lines causes up-regulation of ABCA1 expression and increased cholesterol efflux, and injection of mice on a western-type diet with locked nucleic acid-antisense oligonucleotides results in elevated plasma HDL. Our findings indicate that miR-33 acts in concert with the SREBP host genes to control cholesterol homeostasis and suggest that miR-33 may represent a therapeutic target for ameliorating cardiometabolic diseases.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                14 April 2014
                : 9
                : 4
                : e94997
                Affiliations
                [1 ]Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
                [2 ]Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
                [3 ]Department of Vascular Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
                Harvard Medical School, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: YWH LZ QW. Performed the experiments: YWH YRH SGW JYZ SFL XM YRQ JBL YHS JJG YCW. Analyzed the data: YWH LZ QW. Contributed reagents/materials/analysis tools: YWH YRH. Wrote the paper: YWH YRH SGW. Obtained permission for use of cell line: YWH.

                Article
                PONE-D-14-03118
                10.1371/journal.pone.0094997
                3986368
                24733347
                25cecc52-6174-48f3-8a6a-24a719bc3540
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 22 January 2014
                : 20 March 2014
                Page count
                Pages: 12
                Funding
                The authors gratefully acknowledge financial support from the National Natural Sciences Foundation of China (81301489 and 81271905), Guangdong Provincial Natural Sciences Foundation of China (S2012020010920), and the President Foundation of Nanfang Hospital, Southern Medical University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Biophysics
                Cell Biology
                Molecular Cell Biology
                Physical Sciences
                Physics
                Classical Mechanics

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