2024
Mitochondrial network remodeling of the diabetic heart: implications to ischemia related cardiac dysfunction
Rudokas M, McKay M, Toksoy Z, Eisen J, Bögner M, Young L, Akar F. Mitochondrial network remodeling of the diabetic heart: implications to ischemia related cardiac dysfunction. Cardiovascular Diabetology 2024, 23: 261. PMID: 39026280, PMCID: PMC11264840, DOI: 10.1186/s12933-024-02357-1.Peer-Reviewed Original ResearchConceptsReactive oxygen speciesMitochondrial network remodelingDamaged mitochondrial DNAEfficiency of oxidative phosphorylationImpaired ATP productionMitochondrial ultrastructural alterationsCardiac functionDiabetic heartCellular energy metabolismProduction of reactive oxygen speciesMitochondrial DNAMitochondrial networkMitochondrial fissionExcessive production of reactive oxygen speciesOxidative phosphorylationATP productionResponse to ischemic insultGlobal cardiac functionCell deathOverall cardiac functionCardiac ischemic injuryResponse to injuryCardiac mitochondriaIrreversible cell deathMitochondriaQuantitative Assessment of Mitochondrial Morphology and Electrophysiological Function in the Diabetic Heart
Cacheux M, Rudokas M, Tieu A, Rizk J, Hummel M, Akar F. Quantitative Assessment of Mitochondrial Morphology and Electrophysiological Function in the Diabetic Heart. Methods In Molecular Biology 2024, 2803: 75-86. PMID: 38676886, DOI: 10.1007/978-1-0716-3846-0_6.Peer-Reviewed Original ResearchMeSH KeywordsAction PotentialsAnimalsDiabetes Mellitus, ExperimentalElectrophysiological PhenomenaMitochondria, HeartMyocardiumMyocytes, CardiacRatsConceptsMitochondrial shapeMitochondrial networkMitochondrial architectureSubcellular localizationMitochondrial morphologyDiabetic heartOxidative phosphorylationATP synthesisAction potentialsSarcolemmal ion channelsExcitation-contraction couplingFission eventsOptical action potentialsExcitation-contractionCardiac myocytesElectrophysiological properties
2022
Atrial AMP-activated protein kinase is critical for prevention of dysregulation of electrical excitability and atrial fibrillation
Su KN, Ma Y, Cacheux M, Ilkan Z, Raad N, Muller GK, Wu X, Guerrera N, Thorn SL, Sinusas AJ, Foretz M, Viollet B, Akar JG, Akar FG, Young LH. Atrial AMP-activated protein kinase is critical for prevention of dysregulation of electrical excitability and atrial fibrillation. JCI Insight 2022, 7: e141213. PMID: 35451373, PMCID: PMC9089788, DOI: 10.1172/jci.insight.141213.Peer-Reviewed Original ResearchMeSH KeywordsAMP-Activated Protein KinasesAnimalsAtrial FibrillationAtrial RemodelingConnexinsIon ChannelsMiceMyocytes, CardiacTranscription FactorsConceptsTranscription factorsKey transcription factorMaster metabolic regulatorIon channel subunitsGap junction proteinTranscriptional reprogrammingAMPK deletionProtein kinaseBiological functionsTranscriptional downregulationMetabolic regulatorChannel subunitsIon channelsAMPK expressionMetabolic stressAtrial fibrillationAMPKJunction proteinsElectrical excitabilityHomeostatic roleStructural remodelingConnexinsAtrial ion channelsRemodelingDownregulation
2019
Cardiomyocyte-Specific STIM1 (Stromal Interaction Molecule 1) Depletion in the Adult Heart Promotes the Development of Arrhythmogenic Discordant Alternans
Cacheux M, Strauss B, Raad N, Ilkan Z, Hu J, Benard L, Feske S, Hulot JS, Akar FG. Cardiomyocyte-Specific STIM1 (Stromal Interaction Molecule 1) Depletion in the Adult Heart Promotes the Development of Arrhythmogenic Discordant Alternans. Circulation Arrhythmia And Electrophysiology 2019, 12: e007382-e007382. PMID: 31726860, PMCID: PMC6867678, DOI: 10.1161/circep.119.007382.Peer-Reviewed Original ResearchConceptsVT/VFAPD alternansStore-operated CaVentricular tachycardia/ventricular fibrillationOptical action potential mappingAdult heartVT/Adult murine modelDiscordant alternansConduction velocity slowingSarcoplasmic reticulum CaArrhythmogenic discordant alternansInitial beatsEarly mortalityFlox/Poor survivalVentricular fibrillationDiscordant APD alternansMurine modelCardiac hypertrophyConduction velocityLittermate controlsAdult miceRapid pacingElectrophysiological substrate
2014
Effect of bortezomib on the efficacy of AAV9.SERCA2a treatment to preserve cardiac function in a rat pressure-overload model of heart failure
Chaanine A, Nonnenmacher M, Kohlbrenner E, Jin D, Kovacic J, Akar F, Hajjar R, Weber T. Effect of bortezomib on the efficacy of AAV9.SERCA2a treatment to preserve cardiac function in a rat pressure-overload model of heart failure. Gene Therapy 2014, 21: 379-386. PMID: 24572786, PMCID: PMC3976435, DOI: 10.1038/gt.2014.7.Peer-Reviewed Original ResearchConceptsHeart failureCardiac functionRodent heart failure modelsRat cardiomyocytesHeart failure modelPressure overload modelEffect of bortezomibProteasome inhibitor bortezomibNeonatal rat cardiomyocytesAdult rat cardiomyocytesWestern blot analysisSERCA2a proteinPressure-volume analysisSERCA2a levelsBortezomib treatmentConcurrent treatmentSERCA2a mRNAInhibitor bortezomibBortezomibHeart samplesHuman SERCA2aSerotype 1Proteasome inhibitorsAAV serotypes 1Proteasome inhibition
2011
Mitochondria are sources of metabolic sink and arrhythmias
Akar FG, O'Rourke B. Mitochondria are sources of metabolic sink and arrhythmias. Pharmacology & Therapeutics 2011, 131: 287-294. PMID: 21513732, PMCID: PMC3138548, DOI: 10.1016/j.pharmthera.2011.04.005.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsArrhythmias, CardiacCalciumHumansMitochondria, HeartMyocytes, CardiacSignal Transduction
2010
A brighter side of ROS revealed by selective activation of β‐adrenergic receptor subtypes
Biary N, Akar FG. A brighter side of ROS revealed by selective activation of β‐adrenergic receptor subtypes. The Journal Of Physiology 2010, 588: 2973-2974. PMID: 20710039, PMCID: PMC2956937, DOI: 10.1113/jphysiol.2010.195743.Commentaries, Editorials and LettersAdrenergic beta-1 Receptor AgonistsAdrenergic beta-2 Receptor AgonistsAnimalsGTP-Binding Protein alpha Subunits, Gi-GoHomeostasisHumansMyocytes, CardiacNitric OxideNitric Oxide Synthase Type IIIOxygenRatsReactive Oxygen SpeciesReceptors, Adrenergic, beta-1Receptors, Adrenergic, beta-2Signal TransductionAltered Spatiotemporal Dynamics of the Mitochondrial Membrane Potential in the Hypertrophied Heart
Jin H, Nass RD, Joudrey PJ, Lyon AR, Chemaly ER, Rapti K, Akar FG. Altered Spatiotemporal Dynamics of the Mitochondrial Membrane Potential in the Hypertrophied Heart. Biophysical Journal 2010, 98: 2063-2071. PMID: 20483313, PMCID: PMC2872265, DOI: 10.1016/j.bpj.2010.01.045.Peer-Reviewed Original Research
2009
Electrophysiological Consequences of Dyssynchronous Heart Failure and Its Restoration by Resynchronization Therapy
Aiba T, Hesketh GG, Barth AS, Liu T, Daya S, Chakir K, Dimaano VL, Abraham TP, O'Rourke B, Akar FG, Kass DA, Tomaselli GF. Electrophysiological Consequences of Dyssynchronous Heart Failure and Its Restoration by Resynchronization Therapy. Circulation 2009, 119: 1220-1230. PMID: 19237662, PMCID: PMC2703676, DOI: 10.1161/circulationaha.108.794834.Peer-Reviewed Original ResearchMeSH KeywordsAction PotentialsAnimalsBundle-Branch BlockCalciumCalcium ChannelsCoronary CirculationDogsEchocardiographyElectrocardiographyHeart FailureHomeostasisKv Channel-Interacting ProteinsMaleMyocytes, CardiacPacemaker, ArtificialPatch-Clamp TechniquesPotassium Channels, Inwardly RectifyingRNA, MessengerSarcoplasmic Reticulum Calcium-Transporting ATPasesShal Potassium ChannelsConceptsCardiac resynchronization therapyAction potential durationRight atrial pacingCalcium transient amplitudeHeart failurePotential durationResynchronization therapyAtrial pacingElectrophysiological consequencesLeft bundle-branch ablationTransient amplitudeSarcoplasmic reticulumWhole-cell patch clampDyssynchronous heart failureProtein levelsIon channel remodelingSame pacing rateLeft ventricular anteriorQuantitative polymerase chain reactionSurvival benefitBiventricular pacingVentricular arrhythmiasDyssynchronous contractionPolymerase chain reactionElectrophysiological changes
2008
Mechanisms of Disease: ion channel remodeling in the failing ventricle
Nass RD, Aiba T, Tomaselli GF, Akar FG. Mechanisms of Disease: ion channel remodeling in the failing ventricle. Nature Clinical Practice Cardiovascular Medicine 2008, 5: 196-207. PMID: 18317475, DOI: 10.1038/ncpcardio1130.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus Statements
2007
The Perfect Storm
Akar FG. The Perfect Storm. Circulation Research 2007, 101: 968-970. PMID: 17991890, DOI: 10.1161/circresaha.107.164426.Commentaries, Editorials and LettersMitochondrial Ion Channels in Cardiac Function and Dysfunction
O'Rourke B, Cortassa S, Akar F, Aon M. Mitochondrial Ion Channels in Cardiac Function and Dysfunction. Novartis Foundation Symposia 2007, 287: 140-156. PMID: 18074636, PMCID: PMC2692520, DOI: 10.1002/9780470725207.ch10.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsMeSH KeywordsAnimalsHeartHumansIon ChannelsMembrane Potential, MitochondrialMitochondria, HeartMyocytes, CardiacReactive Nitrogen SpeciesConceptsMitochondrial ion channelsIon channelsReactive oxygen species (ROS) signalsNumerous signaling pathwaysBurst of ROSMitochondrial networkMitochondrial physiologyPlasma membraneSpecies signalSignaling pathwaysCellular activitiesCellular targetsMitochondrial functionEnergy transductionMitochondriaVast modificationsPhysiological conditionsOrgan levelDisease developmentPotential therapeutic interventionsWidespread effectsImportant targetSurprising insightsKey roleCenter of organizations
2005
The mitochondrial origin of postischemic arrhythmias
Akar FG, Aon MA, Tomaselli GF, O'Rourke B. The mitochondrial origin of postischemic arrhythmias. Journal Of Clinical Investigation 2005, 115: 3527-3535. PMID: 16284648, PMCID: PMC1280968, DOI: 10.1172/jci25371.Peer-Reviewed Original ResearchMeSH KeywordsAction PotentialsAnimalsAnionsArrhythmias, CardiacDose-Response Relationship, DrugElectrophysiologyGuinea PigsHeartIntracellular MembranesIon ChannelsIschemiaMembrane PotentialsMicroscopy, ConfocalMitochondria, HeartMyocardial IschemiaMyocardial ReperfusionMyocardial Reperfusion InjuryMyocardiumMyocytes, CardiacOscillometryReactive Oxygen SpeciesReceptors, GABA-AReperfusion InjuryTemperatureTime FactorsConceptsAction potentialsVentricular fibrillationPostischemic functional recoveryIschemic heart diseaseGuinea pig heartsNew therapeutic targetsAbnormal electrical activationPostischemic arrhythmiasReperfusion arrhythmiasFunctional recoveryGlobal ischemiaHeart diseaseBolus infusionArrhythmia preventionElectrophysiological changesAP shorteningControl heartsPostischemic heartsBenzodiazepine receptorsElectrophysiological substrateTherapeutic targetArrhythmiasReperfusionPig heartsMitochondrial benzodiazepine receptor
2004
Functional Integration of Electrically Active Cardiac Derivatives From Genetically Engineered Human Embryonic Stem Cells With Quiescent Recipient Ventricular Cardiomyocytes
Xue T, Cho HC, Akar FG, Tsang SY, Jones SP, Marbán E, Tomaselli GF, Li RA. Functional Integration of Electrically Active Cardiac Derivatives From Genetically Engineered Human Embryonic Stem Cells With Quiescent Recipient Ventricular Cardiomyocytes. Circulation 2004, 111: 11-20. PMID: 15611367, DOI: 10.1161/01.cir.0000151313.18547.a2.Peer-Reviewed Original ResearchMeSH KeywordsAction PotentialsAdrenergic beta-AgonistsAnimalsCell DifferentiationCell FusionCells, CulturedDefective VirusesElectrophysiologyFemaleGenes, ReporterGenetic VectorsGiant CellsGreen Fluorescent ProteinsGuinea PigsHeartHeart Conduction SystemHeart VentriclesHIV-1HumansIsoproterenolLidocaineMiceMyocardial ContractionMyocytes, CardiacOrgan Culture TechniquesPericardiumPluripotent Stem CellsPyrimidinesRatsTransduction, GeneticConceptsVentricular cardiomyocytesCardiac impulse generationBeta-adrenergic agonist isoproterenolGuinea pig heartsSite of injectionStem cellsHuman embryonic stem cellsCell-based therapiesContractile activityAgonist isoproterenolPharmacological agentsVentricular myocardiumLeft ventricleEx vivoDonor cardiomyocytesPig heartsHuman cardiomyocytesRecombinant lentivirusMembrane depolarizationCardiomyocytesFunctional syncytiumImpulse generationEmbryonic stem cellsMyocardiumEpicardial surfaceMechanisms Underlying Conduction Slowing and Arrhythmogenesis in Nonischemic Dilated Cardiomyopathy
Akar FG, Spragg DD, Tunin RS, Kass DA, Tomaselli GF. Mechanisms Underlying Conduction Slowing and Arrhythmogenesis in Nonischemic Dilated Cardiomyopathy. Circulation Research 2004, 95: 717-725. PMID: 15345654, DOI: 10.1161/01.res.0000144125.61927.1c.Peer-Reviewed Original ResearchMeSH KeywordsAction PotentialsAnimalsArrhythmias, CardiacBlotting, WesternCadherinsCardiac Pacing, ArtificialCardiomyopathy, DilatedCell SizeConnexin 43DogsFibrosisGap JunctionsHeart Conduction SystemMicroscopy, ConfocalMicroscopy, FluorescenceMyocardiumMyocytes, CardiacNeural ConductionPatch-Clamp TechniquesPhosphorylationProtein Processing, Post-TranslationalSubcellular Fractions
2003
Phenotypic differences in transient outward K+ current of human and canine ventricular myocytes: insights into molecular composition of ventricular Ito
Akar FG, Wu RC, Deschenes I, Armoundas AA, Piacentino V, Houser SR, Tomaselli GF. Phenotypic differences in transient outward K+ current of human and canine ventricular myocytes: insights into molecular composition of ventricular Ito. AJP Heart And Circulatory Physiology 2003, 286: h602-h609. PMID: 14527940, DOI: 10.1152/ajpheart.00673.2003.Peer-Reviewed Original ResearchConceptsTransient outwardPhenotypic differencesKv channel-interacting proteinsIndependent transient outwardChannel-interacting proteinsProtein chemical techniquesSteady-state inactivationCanine ventricular myocytesWestern blot analysisElectrical remodelingChannel subunit genesMonoexponential time coursePharmacological sensitivityVentricular repolarizationCardiac diseaseElectrophysiological roleCanine ventricularHuman cardiac diseasePosttranslational modificationsVentricular myocytesSubunit genePharmacological propertiesDiseased heartPhenotypic propertiesOxidative stress