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      Impact of miRNA in Atherosclerosis

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          Abstract

          <p class="first" id="P1">MicroRNAs (miRNAs) have received most of the attention over the last decades in particular for their role in tempering gene expression. An increasing number of studies highlighting the importance of miRNAs in the development and progression of atherosclerosis have been performed. Recently, it was shown that miRNAs exert their role in the pathophysiology of atherosclerosis via the regulation of atherosclerosis-prone genes as well as their impact in regulating post-transcriptional gene expression. Hence, by affecting the level of synthesised protein within cells, they may be significant in driving the dysregulation that affects endothelial cells, smooth muscle cells and leukocytes, which initiates and augments the growth of an atherosclerotic plaque. Furthermore, the circulating levels of vascular cell-enriched miRNAs in patients could serve as a marker of disease severity and phenotypes. The accumulating evidence also indicates that their effects on atherosclerosis may allow us to exploit miRNAs as novel therapeutics or clinical biomarkers that may lead to better management of vascular diseases. Current reports providing insights into the impact of miRNAs and the mechanisms of their influences in atherosclerosis are reviewed here with a particular emphasis on studies that have been recently published in Arteriosclerosis, Thrombosis, and Vascular Biology. </p>

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          Most cited references130

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          Most mammalian mRNAs are conserved targets of microRNAs.

          MicroRNAs (miRNAs) are small endogenous RNAs that pair to sites in mRNAs to direct post-transcriptional repression. Many sites that match the miRNA seed (nucleotides 2-7), particularly those in 3' untranslated regions (3'UTRs), are preferentially conserved. Here, we overhauled our tool for finding preferential conservation of sequence motifs and applied it to the analysis of human 3'UTRs, increasing by nearly threefold the detected number of preferentially conserved miRNA target sites. The new tool more efficiently incorporates new genomes and more completely controls for background conservation by accounting for mutational biases, dinucleotide conservation rates, and the conservation rates of individual UTRs. The improved background model enabled preferential conservation of a new site type, the "offset 6mer," to be detected. In total, >45,000 miRNA target sites within human 3'UTRs are conserved above background levels, and >60% of human protein-coding genes have been under selective pressure to maintain pairing to miRNAs. Mammalian-specific miRNAs have far fewer conserved targets than do the more broadly conserved miRNAs, even when considering only more recently emerged targets. Although pairing to the 3' end of miRNAs can compensate for seed mismatches, this class of sites constitutes less than 2% of all preferentially conserved sites detected. The new tool enables statistically powerful analysis of individual miRNA target sites, with the probability of preferentially conserved targeting (P(CT)) correlating with experimental measurements of repression. Our expanded set of target predictions (including conserved 3'-compensatory sites), are available at the TargetScan website, which displays the P(CT) for each site and each predicted target.
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            Atherosclerosis — An Inflammatory Disease

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              Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets.

              We predict regulatory targets of vertebrate microRNAs (miRNAs) by identifying mRNAs with conserved complementarity to the seed (nucleotides 2-7) of the miRNA. An overrepresentation of conserved adenosines flanking the seed complementary sites in mRNAs indicates that primary sequence determinants can supplement base pairing to specify miRNA target recognition. In a four-genome analysis of 3' UTRs, approximately 13,000 regulatory relationships were detected above the estimate of false-positive predictions, thereby implicating as miRNA targets more than 5300 human genes, which represented 30% of our gene set. Targeting was also detected in open reading frames. In sum, well over one third of human genes appear to be conserved miRNA targets.
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                Author and article information

                Journal
                Arteriosclerosis, Thrombosis, and Vascular Biology
                ATVB
                Ovid Technologies (Wolters Kluwer Health)
                1079-5642
                1524-4636
                September 2018
                September 2018
                : 38
                : 9
                Affiliations
                [1 ]From the Center of Clinical Pharmacology (Y.L.)
                [2 ]School of Cardiovascular Medicine and Sciences, King’s College London British Heart Foundation Centre, United Kingdom (T.T., W.G., Q.X.).
                [3 ]Department of Cardiology (J.C., Q.X.), Third Xiangya Hospital, Central South University, Changsha, China
                Article
                10.1161/ATVBAHA.118.310227
                6795547
                30354259
                968905aa-adea-4d2c-8a47-b5511cea949d
                © 2018
                History

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