NF-B-mediated metabolic remodelling in the inflamed heart in acute viral myocarditis
article
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. Chemicals / CAS 3 hydroxyacyl coenzyme A dehydrogenase, 9028-40-4; adenosine diphosphate, 20398-34-9, 58-64-0; adenosine phosphate, 61-19-8, 8063-98-7; arachidonic acid, 506-32-1, 6610-25-9, 7771-44-0; cytochrome c oxidase, 72841-18-0, 9001-16-5; glucose transporter 1, 172077-08-6; intercellular adhesion molecule 1, 126547-89-5; lactate dehydrogenase, 9001-60-9; long chain acyl coenzyme A dehydrogenase, 59536-74-2; nicotinamide adenine dinucleotide, 53-84-9; peroxisome proliferator activated receptor alpha, 147258-70-6; Muscle Proteins; NF-kappa B; peroxisome-proliferator-activated receptor-gamma coactivator-1; PPAR gamma; Transcription Factors
Topics
InflammationMetabolic remodellingMitochondrial oxidative metabolismNF-?BPGC-1Viral myocarditis3 hydroxyacyl coenzyme A dehydrogenaseadenine nucleotideadenosine diphosphateadenosine phosphatearachidonic acidcarbonate dehydratase IXcardiolipincytochrome c oxidaseglucose transporter 1heme oxygenase 1hypoxia inducible factor 1alphaimmunoglobulin enhancer binding proteinintercellular adhesion molecule 1lactate dehydrogenaselactate dehydrogenase 1long chain acyl coenzyme A dehydrogenasemonocarboxylate transporter 4nicotinamide adenine dinucleotideperoxisome proliferator activated receptor alphaphosphatidylinositoltranscriptometumor necrosis factorunclassified drugimmunoglobulin enhancer binding proteinmuscle proteinperoxisome proliferator activated receptor gammaperoxisome-proliferator-activated receptor-gamma coactivator-1transcription factoraerobic metabolismanimal experimentanimal modelanimal tissuecardiac muscle cellcitric acid cyclecontrolled studydown regulationenergy metabolismenzyme activityfatty acid oxidationgene expressiongene targetingheart muscle biopsyheart tissuehigh energy phosphatemass spectrometrymetabolismmousenonhumanoxidative phosphorylationrespiratory chainsignal transductiontranscriptomicstransient transfectionvirus loadvirus myocarditisCoxsackie virus infectiondisease modelEnterovirus BpathologyvirologyAcute DiseaseAnimalsCoxsackievirus InfectionsDisease Models, AnimalEnterovirus B, HumanFemaleGene Expression ProfilingGene Expression RegulationHumansMaleMiceMuscle ProteinsMyocarditisNF-kappa BPPAR gammaTranscription Factors
TNO Identifier
954977
ISSN
09254439
Source
Biochimica et Biophysica Acta - Molecular Basis of Disease, 1864(8), pp. 2579-2589.
Pages
2579-2589