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Cardiovasc Res. 2015 Jul 1;107(1):78-88. doi: 10.1093/cvr/cvv157. Epub 2015 May 21.

Liver X receptor activation enhances CVB3 viral replication during myocarditis by stimulating lipogenesis.

Author information

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.

KEYWORDS:

Inflammation; Lipids; Liver X receptors; Myocarditis; Viral replication

PMID:
25998987
DOI:
10.1093/cvr/cvv157
[Indexed for MEDLINE]

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