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      Transcriptome analysis defines myocardium gene signatures in children with ToF and ASD and reveals disease-specific molecular reprogramming in response to surgery with cardiopulmonary bypass


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          Tetralogy of Fallot (ToF) and Atrial Septal Defects (ASD) are the most common types of congenital heart diseases and a major cause of childhood morbidity and mortality. Cardiopulmonary bypass (CPB) is used during corrective cardiac surgery to support circulation and heart stabilization. However, this procedure triggers systemic inflammatory and stress response and consequent increased risk of postoperative complications. The aim of this study was to define the molecular bases of ToF and ASD pathogenesis and response to CPB and identify new potential biomarkers.


          Comparative transcriptome analysis of right atrium specimens collected from 10 ToF and 10 ASD patients was conducted before (Pre-CPB) and after (Post-CPB) corrective surgery. Total RNA isolated from each sample was individually hybridized on Affymetrix HG-U133 Plus Array Strips containing 38,500 unique human genes. Differences in the gene expression profiles and functional enrichment/network analyses were assessed using bioinformatic tools. qRT-PCR analysis was used to validate gene modulation.


          Pre-CPB samples showed significant differential expression of a total of 72 genes, 28 of which were overexpressed in ToF and 44 in ASD. According to Gene Ontology annotation, the mostly enriched biological processes were represented by matrix organization and cell adhesion in ToF and by muscle development and contractility in ASD specimens. GSEA highlighted the specific enrichment of hypoxia gene sets in ToF samples, pointing to a role for hypoxia in disease pathogenesis. The post-CPB myocardium exhibited significant alterations in the expression profile of genes related to transcription regulation, growth/apoptosis, inflammation, adhesion/matrix organization, and oxidative stress. Among them, only 70 were common to the two disease groups, whereas 110 and 24 were unique in ToF and ASD, respectively. Multiple functional interactions among differentially expressed gene products were predicted by network analysis. Interestingly, gene expression changes in ASD samples followed a consensus hypoxia profile.


          Our results provide a comprehensive view of gene reprogramming in right atrium tissues of ToF and ASD patients before and after CPB, defining specific molecular pathways underlying disease pathophysiology and myocardium response to CPB. These findings have potential translational value because they identify new candidate prognostic markers and targets for tailored cardioprotective post-surgical therapies.

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          Altered microRNA expression in human heart disease.

          MicroRNAs are recently discovered regulators of gene expression and are becoming increasingly recognized as important regulators of heart function. Genome-wide profiling of microRNAs in human heart failure has not been reported previously. We measured expression of 428 microRNAs in 67 human left ventricular samples belonging to control (n = 10), ischemic cardiomyopathy (ICM, n = 19), dilated cardiomyopathy (DCM, n = 25), or aortic stenosis (AS, n = 13) diagnostic groups. miRNA expression between disease and control groups was compared by ANOVA with Dunnett's post hoc test. We controlled for multiple testing by estimating the false discovery rate. Out of 428 microRNAs measured, 87 were confidently detected; 43 were differentially expressed in at least one disease group. In supervised clustering, microRNA expression profiles correctly grouped samples by their clinical diagnosis, indicating that microRNA expression profiles are distinct between diagnostic groups. This was further supported by class prediction approaches, in which the class (control, ICM, DCM, AS) predicted by a microRNA-based classifier matched the clinical diagnosis 69% of the time (P < 0.001). These data show that expression of many microRNAs is altered in heart disease and that different types of heart disease are associated with distinct changes in microRNA expression. These data will guide further studies of the contribution of microRNAs to heart disease pathogenesis.
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            MicroRNA-21 in cardiovascular disease.

            MicroRNA-21 (miR-21) is a highly expressed microRNA (miRNA) in cardiovascular system. Recent studies have revealed that its expression is deregulated in heart and vasculature under cardiovascular disease conditions such as proliferative vascular disease, cardiac hypertrophy and heart failure, and ischemic heart disease. miR-21 is found to play important roles in vascular smooth muscle cell proliferation and apoptosis, cardiac cell growth and death, and cardiac fibroblast functions. Accordingly, miR-21 is proven to be involved in the pathogenesis of the above-mentioned cardiovascular diseases as demonstrated by both loss-of-function and gain-of-function approaches. Programmed cell death 4 (PDCD4), phosphatase and tensin homology deleted from chromosome 10 (PTEN), sprouty1 (SPRY1), and sprouty2 (SPRY2) are the current identified target genes of miR-21 that are involved in miR-21-mediated cardiovascular effects. miR-21 might be a novel therapeutic target in cardiovascular diseases. This review article summarizes the research progress regarding the roles of miR-21 in cardiovascular disease.
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              Loss of MCL-1 leads to impaired autophagy and rapid development of heart failure.

              Myeloid cell leukemia-1 (MCL-1) is an anti-apoptotic BCL-2 protein that is up-regulated in several human cancers. MCL-1 is also highly expressed in myocardium, but its function in myocytes has not been investigated. We generated inducible, cardiomyocyte-specific Mcl-1 knockout mice and found that ablation of Mcl-1 in the adult heart led to rapid cardiomyopathy and death. Although MCL-1 is known to inhibit apoptosis, this process was not activated in MCL-1-deficient hearts. Ultrastructural analysis revealed disorganized sarcomeres and swollen mitochondria in myocytes. Mitochondria isolated from MCL-1-deficient hearts exhibited reduced respiration and limited Ca(2+)-mediated swelling, consistent with opening of the mitochondrial permeability transition pore (mPTP). Double-knockout mice lacking MCL-1 and cyclophilin D, an essential regulator of the mPTP, exhibited delayed progression to heart failure and extended survival. Autophagy is normally induced by myocardial stress, but induction of autophagy was impaired in MCL-1-deficient hearts. These data demonstrate that MCL-1 is essential for mitochondrial homeostasis and induction of autophagy in the heart. This study also raises concerns about potential cardiotoxicity for chemotherapeutics that target MCL-1.

                Author and article information

                J Transl Med
                J Transl Med
                Journal of Translational Medicine
                BioMed Central (London )
                10 January 2020
                10 January 2020
                : 18
                [1 ]GRID grid.419504.d, ISNI 0000 0004 1760 0109, Laboratory of Molecular Biology, , IRCSS Istituto Giannina Gaslini, ; Padiglione 2, L.go G.Gaslini 5, 16147 Genova, Italy
                [2 ]GRID grid.419504.d, ISNI 0000 0004 1760 0109, Department of Cardiology, , IRCSS Istituto Giannina Gaslini, ; Genova, Italy
                [3 ]GRID grid.5606.5, ISNI 0000 0001 2151 3065, Present Address: Department of Internal Medicine, , University of Genova, ; Genova, Italy
                [4 ]GRID grid.462410.5, ISNI 0000 0004 0386 3258, Present Address: INSERM U955 Equipe 16, ; Creteil, France
                [5 ]GRID grid.18887.3e, ISNI 0000000417581884, Present Address: Immunobiology of Neurological Disorders Unit, Institute of Experimental Neurology INSPE, , Ospedale San Raffaele, ; Milano, Italy
                [6 ]GRID grid.419504.d, ISNI 0000 0004 1760 0109, Present Address: Cytomorphology Laboratory, Heamo-Onco-TMO Department, , IRCSS Istituto Giannina Gaslini, ; Genova, Italy
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                Funded by: FundRef http://dx.doi.org/10.13039/501100004710, Fondazione Umberto Veronesi;
                Funded by: Italian Ministry of Health
                Custom metadata
                © The Author(s) 2020

                gene expression profiling,congenital heart disease,cardiopulmonary bypass,atrial myocardium,hypoxia


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