Network analysis reveals a causal role of mitochondrial gene activity in atherosclerotic lesion formation.

Autor: Vilne B; Deutsches Herzzentrum München, Klinik für Herz- und Kreislauferkrankungen, Technische Universität München, Munich, Germany; DZHK (German Research Centre for Cardiovascular Research), Munich Heart Alliance, Munich, Germany., Skogsberg J; Cardiovascular Genomics Group, Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden., Foroughi Asl H; Cardiovascular Genomics Group, Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden., Talukdar HA; Cardiovascular Genomics Group, Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden; Integrated Cardio Metabolic Center (ICMC), Karolinska Institutet, 141 57 Huddinge, Sweden., Kessler T; Deutsches Herzzentrum München, Klinik für Herz- und Kreislauferkrankungen, Technische Universität München, Munich, Germany; DZHK (German Research Centre for Cardiovascular Research), Munich Heart Alliance, Munich, Germany., Björkegren JLM; Cardiovascular Genomics Group, Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden; Department of Physiology, Institute of Biomedicine and Translation Medicine, University of Tartu, Estonia; Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai New York, New York, USA; Clinical Gene Networks AB, Stockholm, Sweden. Electronic address: johan.bjorkegren@mssm.edu., Schunkert H; Deutsches Herzzentrum München, Klinik für Herz- und Kreislauferkrankungen, Technische Universität München, Munich, Germany; DZHK (German Research Centre for Cardiovascular Research), Munich Heart Alliance, Munich, Germany. Electronic address: schunkert@dhm.mhn.de.
Jazyk: angličtina
Zdroj: Atherosclerosis [Atherosclerosis] 2017 Dec; Vol. 267, pp. 39-48. Date of Electronic Publication: 2017 Oct 21.
DOI: 10.1016/j.atherosclerosis.2017.10.019
Abstrakt: Background and Aims: Mitochondrial damage and augmented production of reactive oxygen species (ROS) may represent an intermediate step by which hypercholesterolemia exacerbates atherosclerotic lesion formation.
Methods: To test this hypothesis, in mice with severe but genetically reversible hypercholesterolemia (i.e. the so called Reversa mouse model), we performed time-resolved analyses of mitochondrial transcriptome in the aortic arch employing a systems-level network approach.
Results: During hypercholesterolemia, we observed a massive down-regulation (>28%) of mitochondrial genes, specifically at the time of rapid atherosclerotic lesion expansion and foam cell formation, i.e. between 30 and 40 weeks of age. Both phenomena - down-regulation of mitochondrial genes and lesion expansion - were largely reversible by genetically lowering plasma cholesterol (by >80%, from 427 to 54 ± 31 mg/L) at 30 weeks. Co-expression network analysis revealed that both mitochondrial signature genes were highly connected in two modules, negatively correlating with lesion size and supported as causal for coronary artery disease (CAD) in humans, as expression-associated single nucleotide polymorphisms (eSNPs) representing their genes overlapped markedly with established disease risk loci. Within these modules, we identified the transcription factor estrogen related receptor (ERR)-α and its co-factors PGC1-α and -β, i.e. two members of the peroxisome proliferator-activated receptor γ co-activator 1 family of transcription regulators, as key regulatory genes. Together, these factors are known as major orchestrators of mitochondrial biogenesis and antioxidant responses.
Conclusions: Using a network approach, we demonstrate how hypercholesterolemia could hamper mitochondrial activity during atherosclerosis progression and pinpoint potential therapeutic targets to counteract these processes.
(Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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