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      Regulation of Gene Expression with Thyroid Hormone in Rats with Myocardial Infarction

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          Abstract

          Introduction

          The expression of hundreds of genes is altered in response to left ventricular (LV) remodeling following large transmural myocardial infarction (MI). Thyroid hormone (TH) improves LV remodeling and cardiac performance after MI. However, the molecular basis is unknown.

          Methods

          MI was produced by ligation of the left anterior descending coronary artery in female SD rats. Rats were divided into the following groups: (1) Sham MI, (2) MI, and (3) MI+T4 treatment (T4 pellet 3.3 mg, 60 days release, implanted subcutaneously immediately following MI). Four weeks after surgery, total RNA was isolated from LV non-infarcted areas for microarray analysis using the Illumina RatRef-12 Expression BeadChip Platform.

          Results

          Signals were detected in 13,188 genes (out of 22,523), of which the expression of 154 genes were decreased and the expression of 200 genes were increased in MI rats compared with Sham MI rats (false discovery rate (FDR) <0.05). Compared to MI rats, T4 treatment decreased expression of 27 genes and increased expression of 28 genes. In particular, 6 genes down-regulated by MI and 12 genes up-regulated by MI were reversed by T4. Most of the 55 genes altered by T4 treatment are in the category of molecular function under binding (24) and biological processes which includes immune system process (9), multi-organism process (5) and biological regulation (19) nonexclusively.

          Conclusions

          These results suggest that altered expression of genes for molecular function and biological process may be involved in the beneficial effects of thyroid hormone treatment following MI in rats.

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          Most cited references28

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          Cluster analysis and display of genome-wide expression patterns.

          A system of cluster analysis for genome-wide expression data from DNA microarray hybridization is described that uses standard statistical algorithms to arrange genes according to similarity in pattern of gene expression. The output is displayed graphically, conveying the clustering and the underlying expression data simultaneously in a form intuitive for biologists. We have found in the budding yeast Saccharomyces cerevisiae that clustering gene expression data groups together efficiently genes of known similar function, and we find a similar tendency in human data. Thus patterns seen in genome-wide expression experiments can be interpreted as indications of the status of cellular processes. Also, coexpression of genes of known function with poorly characterized or novel genes may provide a simple means of gaining leads to the functions of many genes for which information is not available currently.
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            Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis.

            Angiogenesis is thought to depend on a precise balance of positive and negative regulation. Angiopoietin-1 (Ang1) is an angiogenic factor that signals through the endothelial cell-specific Tie2 receptor tyrosine kinase. Like vascular endothelial growth factor, Ang1 is essential for normal vascular development in the mouse. An Ang1 relative, termed angiopoietin-2 (Ang2), was identified by homology screening and shown to be a naturally occurring antagonist for Ang1 and Tie2. Transgenic overexpression of Ang2 disrupts blood vessel formation in the mouse embryo. In adult mice and humans, Ang2 is expressed only at sites of vascular remodeling. Natural antagonists for vertebrate receptor tyrosine kinases are atypical; thus, the discovery of a negative regulator acting on Tie2 emphasizes the need for exquisite regulation of this angiogenic receptor system.
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              MicroRNA-208a is a regulator of cardiac hypertrophy and conduction in mice.

              MicroRNAs (miRNAs) are a class of small noncoding RNAs that have gained status as important regulators of gene expression. Here, we investigated the function and molecular mechanisms of the miR-208 family of miRNAs in adult mouse heart physiology. We found that miR-208a, which is encoded within an intron of alpha-cardiac muscle myosin heavy chain gene (Myh6), was actually a member of a miRNA family that also included miR-208b, which was determined to be encoded within an intron of beta-cardiac muscle myosin heavy chain gene (Myh7). These miRNAs were differentially expressed in the mouse heart, paralleling the expression of their host genes. Transgenic overexpression of miR-208a in the heart was sufficient to induce hypertrophic growth in mice, which resulted in pronounced repression of the miR-208 regulatory targets thyroid hormone-associated protein 1 and myostatin, 2 negative regulators of muscle growth and hypertrophy. Studies of the miR-208a Tg mice indicated that miR-208a expression was sufficient to induce arrhythmias. Furthermore, analysis of mice lacking miR-208a indicated that miR-208a was required for proper cardiac conduction and expression of the cardiac transcription factors homeodomain-only protein and GATA4 and the gap junction protein connexin 40. Together, our studies uncover what we believe are novel miRNA-dependent mechanisms that modulate cardiac hypertrophy and electrical conduction.
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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
                2012
                1 August 2012
                : 7
                : 8
                : e40161
                Affiliations
                [1 ]Department of Biomedical Sciences, New York College of Osteopathic Medicine of New York Institute of Technology, Old Westbury, New York, United States of America
                [2 ]Sanford Research/University of South Dakota, Sioux Falls, South Dakota, United States of America
                [3 ]Department of Mathematics and Statistics, South Dakota State University, Brookings, South Dakota, United States of America
                AC Camargo Cancer Hospital, Brazil
                Author notes

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

                Conceived and designed the experiments: YFC AMG. Performed the experiments: YFC NYW OVS. Analyzed the data: YFC JVP XG. Contributed reagents/materials/analysis tools: YFC NYW OVS. Wrote the paper: YFC.

                Article
                PONE-D-12-01309
                10.1371/journal.pone.0040161
                3411604
                22870193
                fcbbf6df-1825-455a-8555-5818d55874b6
                Copyright @ 2012

                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
                : 13 January 2012
                : 1 June 2012
                Page count
                Pages: 9
                Funding
                This study was supported by the National Institutes of Health (NIH) RO1 HL093160-01A1 and RO1 HL103671-01A1, as well as American Heart Association (AHA) MWA Fall 09 Postdoctoral Fellowship 10POST2650057. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Anatomy and Physiology
                Cardiovascular System
                Biochemistry
                Nucleic Acids
                Proteins
                Computational Biology
                Biological Data Management
                Genomics
                Microarrays
                Model Organisms
                Animal Models
                Rat
                Molecular Cell Biology
                Gene Expression

                Uncategorized
                Uncategorized

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