Anna-Pia Papageorgiou1, Ward Heggermont2, Marieke Rienks3, Paolo Carai2, Lies Langouche4, Wouter Verhesen3, Rudolf A De Boer5, Stephane Heymans6. 1. Centre for Molecular and Vascular Biology (CMVB), Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium CArdiovascular Research Institute Maastricht (CARIM), Universiteitssingel 50, 6229 ER Maastricht, The Netherlands anna.papageorgiou@maastrichtuniversity.nl. 2. Centre for Molecular and Vascular Biology (CMVB), Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium CArdiovascular Research Institute Maastricht (CARIM), Universiteitssingel 50, 6229 ER Maastricht, The Netherlands. 3. CArdiovascular Research Institute Maastricht (CARIM), Universiteitssingel 50, 6229 ER Maastricht, The Netherlands. 4. Laboratory of Intensive Care Medicine, KU Leuven, Leuven, Belgium. 5. University Medical Center, Groningen University, Groningen, The Netherlands. 6. Centre for Molecular and Vascular Biology (CMVB), Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium CArdiovascular Research Institute Maastricht (CARIM), Universiteitssingel 50, 6229 ER Maastricht, The Netherlands ICIN - Netherlands Heart Institute, Utrecht, The Netherlands.
Abstract
AIMS: Viral myocarditis (VM) is severe cardiac inflammation that can result in sudden death or congestive heart failure in previously healthy adults, with no effective therapy. Liver X receptor (LXR) agonists have both anti-inflammatory and lipid-lowering properties. This study investigates whether LXR agonist T0901317 may modulate viral replication and cardiac inflammation during VM. METHODS AND RESULTS: (i) Adult mice were administered T0901317 or vehicle with the onset of inflammation during CVB3 virus myocarditis or (ii) treated 2 days prior to CVB3 infection. Against what we expected, T0901317 treatment did not alter leucocyte infiltration after CVB3 infection; yet pre-administration with T0901317 resulted in increased mortality upon CVB3 infection, higher cardiac viral presence, and increased cardiomyocyte damage when compared with the vehicle. Furthermore, we show a correlation of fatty acid synthase (FAS) and sterol regulatory element-binding protein 1c (SREBP-1c) with CVB3 viral load in the heart and that T0901317 is able to enhance the cardiac expression of FAS and SREBP-1c. Finally, we show in vitro that T0901317 is able to exaggerate CVB3-mediated damage of Vero cells, whereas inhibitors of FAS and the SREBP-1c reduce the viral presence of CVB3 in neonatal cardiomyocytes. CONCLUSION: LXR agonism does not modulate cardiac inflammation, but exacerbates virus-mediated myocardial damage during VM by stimulating lipid biosynthesis and enhancing CVB3 replication. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Viral myocarditis (VM) is severe cardiac inflammation that can result in sudden death or congestive heart failure in previously healthy adults, with no effective therapy. Liver X receptor (LXR) agonists have both anti-inflammatory and lipid-lowering properties. This study investigates whether LXR agonist T0901317 may modulate viral replication and cardiac inflammation during VM. METHODS AND RESULTS: (i) Adult mice were administered T0901317 or vehicle with the onset of inflammation during CVB3virus myocarditis or (ii) treated 2 days prior to CVB3infection. Against what we expected, T0901317 treatment did not alter leucocyte infiltration after CVB3infection; yet pre-administration with T0901317 resulted in increased mortality upon CVB3infection, higher cardiac viral presence, and increased cardiomyocyte damage when compared with the vehicle. Furthermore, we show a correlation of fatty acid synthase (FAS) and sterol regulatory element-binding protein 1c (SREBP-1c) with CVB3 viral load in the heart and that T0901317 is able to enhance the cardiac expression of FAS and SREBP-1c. Finally, we show in vitro that T0901317 is able to exaggerate CVB3-mediated damage of Vero cells, whereas inhibitors of FAS and the SREBP-1c reduce the viral presence of CVB3 in neonatal cardiomyocytes. CONCLUSION: LXR agonism does not modulate cardiac inflammation, but exacerbates virus-mediated myocardial damage during VM by stimulating lipid biosynthesis and enhancing CVB3 replication. Published on behalf of the European Society of Cardiology. All rights reserved.