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      Transcriptome Profiling in Systems Vascular Medicine

      research-article
      Frontiers in Pharmacology
      Frontiers Media S.A.
      transcriptome, microarray, RNA-sequencing, vascular medicine, gene profiling, long non-coding RNA

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          Abstract

          In the post-genomic, big data era, our understanding of vascular diseases has been deepened by multiple state-of-the-art “–omics” approaches, including genomics, epigenomics, transcriptomics, proteomics, lipidomics and metabolomics. Genome-wide transcriptomic profiling, such as gene microarray and RNA-sequencing, emerges as powerful research tools in systems medicine and revolutionizes transcriptomic analysis of the pathological mechanisms and therapeutics of vascular diseases. In this article, I will highlight the workflow of transcriptomic profiling, outline basic bioinformatics analysis, and summarize recent gene profiling studies performed in vascular cells as well as in human and mice diseased samples. Further mining of these public repository datasets will shed new light on our understanding of the cellular basis of vascular diseases and offer novel potential targets for therapeutic intervention.

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          Most cited references65

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          Gene Ontology: tool for the unification of biology

          Genomic sequencing has made it clear that a large fraction of the genes specifying the core biological functions are shared by all eukaryotes. Knowledge of the biological role of such shared proteins in one organism can often be transferred to other organisms. The goal of the Gene Ontology Consortium is to produce a dynamic, controlled vocabulary that can be applied to all eukaryotes even as knowledge of gene and protein roles in cells is accumulating and changing. To this end, three independent ontologies accessible on the World-Wide Web (http://www.geneontology.org) are being constructed: biological process, molecular function and cellular component.
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            Antagonism of miR-33 in mice promotes reverse cholesterol transport and regression of atherosclerosis.

            Plasma HDL levels have a protective role in atherosclerosis, yet clinical therapies to raise HDL levels have remained elusive. Recent advances in the understanding of lipid metabolism have revealed that miR-33, an intronic microRNA located within the SREBF2 gene, suppresses expression of the cholesterol transporter ABC transporter A1 (ABCA1) and lowers HDL levels. Conversely, mechanisms that inhibit miR-33 increase ABCA1 and circulating HDL levels, suggesting that antagonism of miR-33 may be atheroprotective. As the regression of atherosclerosis is clinically desirable, we assessed the impact of miR-33 inhibition in mice deficient for the LDL receptor (Ldlr-/- mice), with established atherosclerotic plaques. Mice treated with anti-miR33 for 4 weeks showed an increase in circulating HDL levels and enhanced reverse cholesterol transport to the plasma, liver, and feces. Consistent with this, anti-miR33-treated mice showed reductions in plaque size and lipid content, increased markers of plaque stability, and decreased inflammatory gene expression. Notably, in addition to raising ABCA1 levels in the liver, anti-miR33 oligonucleotides directly targeted the plaque macrophages, in which they enhanced ABCA1 expression and cholesterol removal. These studies establish that raising HDL levels by anti-miR33 oligonucleotide treatment promotes reverse cholesterol transport and atherosclerosis regression and suggest that it may be a promising strategy to treat atherosclerotic vascular disease.
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              Animal models of atherosclerosis.

              An ideal animal model of atherosclerosis resembles human anatomy and pathophysiology and has the potential to be used in medical and pharmaceutical research to obtain results that can be extrapolated to human medicine. Moreover, it must be easy to acquire, can be maintained at a reasonable cost, is easy to handle and shares the topography of the lesions with humans. In general, animal models of atherosclerosis are based on accelerated plaque formation due to a cholesterol-rich/Western-type diet, manipulation of genes involved in the cholesterol metabolism, and the introduction of additional risk factors for atherosclerosis. Mouse and rabbit models have been mostly used, followed by pigs and non-human primates. Each of these models has its advantages and limitations. The mouse has become the predominant species to study experimental atherosclerosis because of its rapid reproduction, ease of genetic manipulation and its ability to monitor atherogenesis in a reasonable time frame. Both Apolipoprotein E deficient (ApoE(-/-)) and LDL-receptor (LDLr) knockout mice have been frequently used, but also ApoE/LDLr double-knockout, ApoE3-Leiden and PCSK9-AAV mice are valuable tools in atherosclerosis research. However, a great challenge was the development of a model in which intra-plaque microvessels, haemorrhages, spontaneous atherosclerotic plaque ruptures, myocardial infarction and sudden death occur consistently. These features are present in ApoE(-/-)Fbn1(C1039G+/-) mice, which can be used as a validated model in pre-clinical studies to evaluate novel plaque-stabilizing drugs.
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                Author and article information

                Contributors
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                25 August 2017
                2017
                : 8
                : 563
                Affiliations
                [1]Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester NY, United States
                Author notes

                Edited by: Weien Yuan, Shanghai Jiao Tong University, China

                Reviewed by: Liborio Stuppia, Università degli Studi “G. d’Annunzio" Chieti – Pescara, Italy; Gaetano Santulli, Columbia University, United States; Kristen J. Bubb, University of Sydney, Australia

                This article was submitted to Translational Pharmacology, a section of the journal Frontiers in Pharmacology

                Article
                10.3389/fphar.2017.00563
                5609594
                28970795
                5723abbe-79b6-4b5e-879b-2e83cc897f18
                Copyright © 2017 Xu.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 10 July 2017
                : 08 August 2017
                Page count
                Figures: 2, Tables: 5, Equations: 0, References: 87, Pages: 9, Words: 0
                Categories
                Pharmacology
                Technology Report

                Pharmacology & Pharmaceutical medicine
                transcriptome,microarray,rna-sequencing,vascular medicine,gene profiling,long non-coding rna

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