title: MDA-5 activation by cytoplasmic double-stranded RNA impairs endothelial function and aggravates atherosclerosis.
abstract: Recent studies have highlighted the relevance of viral nucleic acid immunorecognition by pattern recognition receptors in atherogenesis. Melanoma differentiation associated gene 5 (MDA-5) belongs to the intracellular retinoic acid inducible gene-I like receptors and its activation promotes pro-inflammatory mechanisms. Here, we studied the effect of MDA-5 stimulation in vascular biology. To gain insights into MDA-5 dependent effects on endothelial function, cultured human coronary artery endothelial cells (HCAEC) were transfected with the synthetic MDA-5 agonist polyIC (long double-stranded RNA). Human coronary endothelial cell expressed MDA-5 and reacted with receptor up-regulation upon stimulation. Reactive oxygen species formation, apoptosis and the release of pro-inflammatory cytokines was enhanced, whereas migration was significantly reduced in response to MDA-5 stimulation. To test these effects in vivo, wild-type mice were transfected with 32.5 μg polyIC/JetPEI or polyA/JetPEI as control every other day for 7 days. In polyIC-treated wild-type mice, endothelium-dependent vasodilation and re-endothelialization was significantly impaired, vascular oxidative stress significantly increased and circulating endothelial microparticles and circulating endothelial progenitor cells significantly elevated compared to controls. Importantly, these effects could be abrogated by MDA-5 deficiency in vivo. Finally, chronic MDA-5 stimulation in Apolipoprotein E/toll-like receptor 3 (TLR3) double(-) deficient (ApoE(-/-) /TLR3(-/-) ) mice-enhanced atherosclerotic plaque formation. This study demonstrates that MDA-5 stimulation leads to endothelial dysfunction, and has the potential to aggravate atherosclerotic plaque burden in murine atherosclerosis. Thus, the spectrum of relevant innate immune receptors in vascular diseases and atherogenesis might not be restricted to TLRs but also encompasses the group of RLRs including MDA-5.
authors.affiliation: Department of Medicine/Cardiology, University of Bonn, Bonn, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Asdonk
authors.affiliation: Department of Medicine/Cardiology, University of Bonn, Bonn, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Steinmetz
authors.affiliation: Department of Medicine/Cardiology, University of Bonn, Bonn, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Krogmann
authors.affiliation: Department of Medicine/Cardiology, University of Bonn, Bonn, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Ströcker
authors.affiliation: Department of Medicine/Cardiology, University of Bonn, Bonn, Germany.
authors.forename: Catharina
authors.initials: C
authors.lastname: Lahrmann
authors.affiliation: Department of Medicine/Cardiology, University of Bonn, Bonn, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Motz
authors.affiliation: Department of Medicine/Cardiology, University of Bonn, Bonn, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Paul-Krahe
authors.affiliation: Department of Medicine/Cardiology, University of Bonn, Bonn, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Flender
authors.affiliation: Department of Medicine/Cardiology, University of Bonn, Bonn, Germany.
authors.forename: Theresa
authors.initials: T
authors.lastname: Schmitz
authors.affiliation: Institute for Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany.
authors.forename: Winfried
authors.initials: W
authors.lastname: Barchet
authors.affiliation: Institute for Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany.
authors.forename: Gunther
authors.initials: G
authors.lastname: Hartmann
authors.affiliation: Department of Medicine/Cardiology, University of Bonn, Bonn, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Nickenig
authors.affiliation: Department of Medicine/Cardiology, University of Bonn, Bonn, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Zimmer
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D001057:Apolipoproteins E / Q000172:deficiency / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology*; D015415:Biomarkers / Q000378:metabolism; D002452:Cell Count; D003331:Coronary Vessels / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D000072640:Interferon-Induced Helicase, IFIH1 / Q000172:deficiency / Q000378:metabolism*; D042541:Intracellular Space / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058226:Plaque, Atherosclerotic / Q000378:metabolism / Q000473:pathology; D011070:Poly I-C / Q000494:pharmacology; D012330:RNA, Double-Stranded / Q000494:pharmacology*; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism
chemical_list: D000950:Antigens, Ly; D001057:Apolipoproteins E; D015415:Biomarkers; D016207:Cytokines; D018836:Inflammation Mediators; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D012330:RNA, Double-Stranded; C452815:IFIH1 protein, human; C510592:Ifih1 protein, mouse; D000072640:Interferon-Induced Helicase, IFIH1; D011070:Poly I-C
keywords: Apolipoprotein E; MDA-5; atherosclerosis; endothelial dysfunction; endothelium; inflammation; polyA: reendothelialization; polyIC