NF-κB-mediated metabolic remodelling in the inflamed heart in acute viral myocarditis.

Autor: Remels AHV; Department of Pharmacology and Toxicology, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands. Electronic address: a.remels@maastrichtuniversity.nl., Derks WJA; Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands., Cillero-Pastor B; The Maastricht Multimodal Molecular Imaging institute (M4I), Division of Imaging Mass Spectrometry, Maastricht University, Maastricht, The Netherlands., Verhees KJP; Department of Respiratory Medicine, NUTRIM, Maastricht University, Maastricht, The Netherlands., Kelders MC; Department of Respiratory Medicine, NUTRIM, Maastricht University, Maastricht, The Netherlands., Heggermont W; Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands., Carai P; Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands., Summer G; Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands; TNO, Microbiology & Systems Biology, Zeist, The Netherlands., Ellis SR; The Maastricht Multimodal Molecular Imaging institute (M4I), Division of Imaging Mass Spectrometry, Maastricht University, Maastricht, The Netherlands., de Theije CC; Department of Respiratory Medicine, NUTRIM, Maastricht University, Maastricht, The Netherlands., Heeren RMA; The Maastricht Multimodal Molecular Imaging institute (M4I), Division of Imaging Mass Spectrometry, Maastricht University, Maastricht, The Netherlands., Heymans S; Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands., Papageorgiou AP; Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands., van Bilsen M; Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands; Department of Physiology, CARIM, Maastricht University, Maastricht, The Netherlands.
Jazyk: angličtina
Zdroj: Biochimica et biophysica acta. Molecular basis of disease [Biochim Biophys Acta Mol Basis Dis] 2018 Aug; Vol. 1864 (8), pp. 2579-2589. Date of Electronic Publication: 2018 May 03.
DOI: 10.1016/j.bbadis.2018.04.022
Abstrakt: Acute viral myocarditis (VM), characterised by leukocyte infiltration and dysfunction of the heart, is an important cause of sudden cardiac death in young adults. Unfortunately, to date, the pathological mechanisms underlying cardiac failure in VM remain incompletely understood. In the current study, we investigated if acute VM leads to cardiac metabolic rewiring and if this process is driven by local inflammation. Transcriptomic analysis of cardiac biopsies from myocarditis patients and a mouse model of VM revealed prominent reductions in the expression of a multitude of genes involved in mitochondrial oxidative energy metabolism. In mice, this coincided with reductions in high-energy phosphate and NAD levels, as determined by Imaging Mass Spectrometry, as well as marked decreases in the activity, protein abundance and mRNA levels of various enzymes and key regulators of cardiac oxidative metabolism. Indicative of fulminant cardiac inflammation, NF-κB signalling and inflammatory cytokine expression were potently induced in the heart during human and mouse VM. In cultured cardiomyocytes, cytokine-mediated NF-κB activation impaired cardiomyocyte oxidative gene expression, likely by interfering with the PGC-1 (peroxisome proliferator-activated receptor (PPAR)-γ co-activator) signalling network, the key regulatory pathway controlling cardiomyocyte oxidative metabolism. In conclusion, we provide evidence that acute VM is associated with extensive cardiac metabolic remodelling and our data support a mechanism whereby cytokines secreted primarily from infiltrating leukocytes activate NF-κB signalling in cardiomyocytes thereby inhibiting the transcriptional activity of the PGC-1 network and consequently modulating myocardial energy metabolism.
(Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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