2019
Angiotensin Receptor Neprilysin Inhibitor Attenuates Myocardial Remodeling and Improves Infarct Perfusion in Experimental Heart Failure
Pfau D, Thorn SL, Zhang J, Mikush N, Renaud JM, Klein R, deKemp RA, Wu X, Hu X, Sinusas AJ, Young LH, Tirziu D. Angiotensin Receptor Neprilysin Inhibitor Attenuates Myocardial Remodeling and Improves Infarct Perfusion in Experimental Heart Failure. Scientific Reports 2019, 9: 5791. PMID: 30962467, PMCID: PMC6453892, DOI: 10.1038/s41598-019-42113-0.Peer-Reviewed Original ResearchMeSH KeywordsAminobutyratesAngiotensin Receptor AntagonistsAnimalsBiphenyl CompoundsDrug CombinationsHeartHeart FailureMaleMyocardial Reperfusion InjuryMyocardiumNeovascularization, PhysiologicNeprilysinOrganotechnetium CompoundsPeptides, CyclicRatsRats, Inbred LewSingle Photon Emission Computed Tomography Computed TomographyTetrazolesValsartanVascular Endothelial Growth Factor AVentricular RemodelingConceptsSacubitril/valsartanExperimental heart failureHeart failureMyocardial infarctionMyocardial remodelingAngiotensin receptor neprilysin inhibitorAngiotensin receptor blocker valsartanMicroSPECT/CT imagingReceptor blocker valsartanHeart failure patientsProgressive LV dilationGlobal LV functionLV contractile dysfunctionNeprilysin inhibitor sacubitrilBorder zoneLimited remodelingFailure patientsInhibitor therapyMale LewisWeeks treatmentLV dilationLV functionNeprilysin inhibitorContractile dysfunctionInterstitial fibrosis
2015
AMPK is critical for mitochondrial function during reperfusion after myocardial ischemia
Zaha VG, Qi D, Su KN, Palmeri M, Lee HY, Hu X, Wu X, Shulman GI, Rabinovitch PS, Russell RR, Young LH. AMPK is critical for mitochondrial function during reperfusion after myocardial ischemia. Journal Of Molecular And Cellular Cardiology 2015, 91: 104-113. PMID: 26746142, PMCID: PMC4839186, DOI: 10.1016/j.yjmcc.2015.12.032.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisCatalaseGene Expression RegulationHydrogen PeroxideMAP Kinase Kinase 4MiceMice, Inbred C57BLMice, TransgenicMitochondria, HeartMitochondrial Membrane Transport ProteinsMitochondrial Permeability Transition PoreMyocardial InfarctionMyocardial ReperfusionMyocardiumNecrosisProtein Kinase InhibitorsSignal TransductionTransgenesConceptsWild typeProtein kinase kinase 4Mitochondrial functionMitochondrial catalaseKinase-dead AMPKMitochondrial reactive oxygen productionStress-responsive kinaseMPTP openingC-Jun terminal kinaseInhibition of JNKPermeability transition pore openingMitochondrial permeability transition pore openingTransition pore openingAMPK inactivationResponsive kinaseTerminal kinaseCellular metabolismJNK activationMitochondrial integrityReactive oxygen productionTransgenic expressionCell survivalAMPKKinase 4Kinase
2013
Urocortin 2 autocrine/paracrine and pharmacologic effects to activate AMP-activated protein kinase in the heart
Li J, Qi D, Cheng H, Hu X, Miller EJ, Wu X, Russell KS, Mikush N, Zhang J, Xiao L, Sherwin RS, Young LH. Urocortin 2 autocrine/paracrine and pharmacologic effects to activate AMP-activated protein kinase in the heart. Proceedings Of The National Academy Of Sciences Of The United States Of America 2013, 110: 16133-16138. PMID: 24043794, PMCID: PMC3791748, DOI: 10.1073/pnas.1312775110.Peer-Reviewed Original ResearchMeSH KeywordsAcetyl-CoA CarboxylaseAMP-Activated Protein KinasesAnalysis of VarianceAnimalsAntibodies, NeutralizingCorticotropin-Releasing HormoneEnzyme ActivationImmunoblottingImmunohistochemistryMiceMyocardiumPeptide FragmentsPhosphorylationReceptors, Corticotropin-Releasing HormoneReperfusion InjurySignal TransductionUrocortinsConceptsIschemia/reperfusionIschemia/reperfusion injuryUCN2 treatmentReperfusion injuryContractile dysfunctionRegional ischemia/reperfusionAMPK activationHeart muscleIschemic AMPK activationAutocrine/paracrine pathwayCardiac contractile dysfunctionAutocrine/paracrine factorCorticotropin-releasing factor (CRF) familyIsolated heart muscleCRFR2 antagonistAcetyl-CoA carboxylase phosphorylationCardiac damageMyocardial injuryCRF receptorsPharmacologic effectsUrocortin 2ΕV1-2Activation of AMPParacrine pathwaysReperfusion
2012
AMP-Activated Protein Kinase Regulation and Biological Actions in the Heart
Zaha VG, Young LH. AMP-Activated Protein Kinase Regulation and Biological Actions in the Heart. Circulation Research 2012, 111: 800-814. PMID: 22935535, PMCID: PMC4397099, DOI: 10.1161/circresaha.111.255505.BooksConceptsAMPK pathwayProtein kinase regulationCellular fuel gaugeStress-activated kinasesRegulation of AMPKMaster metabolic regulatorNovel molecular mechanismBiological actionsKinase regulationDiverse biological actionsAMPK regulationProtein kinaseMolecular mechanismsMetabolic regulatorFuel gaugeImportant biological actionsRecent discoveryKinaseAMPKRegulationNew insightsPharmacological activationPathwayImportant roleTherapeutic potential
2010
Risk stratification in diabetes: Not all patients or perfusion defects are the same
Young LH. Risk stratification in diabetes: Not all patients or perfusion defects are the same. Journal Of Nuclear Cardiology 2010, 17: 990-992. PMID: 21042899, DOI: 10.1007/s12350-010-9306-3.Commentaries, Editorials and Letters
2009
Cardiac macrophage migration inhibitory factor inhibits JNK pathway activation and injury during ischemia/reperfusion
Qi D, Hu X, Wu X, Merk M, Leng L, Bucala R, Young LH. Cardiac macrophage migration inhibitory factor inhibits JNK pathway activation and injury during ischemia/reperfusion. Journal Of Clinical Investigation 2009, 119: 3807-3816. PMID: 19920350, PMCID: PMC2786800, DOI: 10.1172/jci39738.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell LineEnzyme ActivationHumansIn Vitro TechniquesIntramolecular OxidoreductasesJNK Mitogen-Activated Protein KinasesMacrophage Migration-Inhibitory FactorsMAP Kinase Kinase 4MiceMice, Inbred BALB CMice, Inbred C57BLMice, KnockoutMyocardial ContractionMyocardial Reperfusion InjuryMyocardiumReceptors, ImmunologicSignal TransductionConceptsMacrophage migration inhibitory factorIschemia/reperfusionMIF deficiencyCardiac injuryMIF allelesJNK pathway activationRole of MIFRecombinant macrophage migration inhibitory factorExperimental ischemia/reperfusionLow-expression MIF allelePathway activationGreater contractile dysfunctionMIF-/- miceMigration inhibitory factorJNK activationReperfusion injuryContractile dysfunctionCoronary occlusionProinflammatory cytokinesWT heartsReperfusionCell death (BAD) phosphorylationInjuryClinical implicationsInhibitory factorAMP‐activated protein kinase: a core signalling pathway in the heart
Kim AS, Miller EJ, Young LH. AMP‐activated protein kinase: a core signalling pathway in the heart. Acta Physiologica 2009, 196: 37-53. PMID: 19239414, DOI: 10.1111/j.1748-1716.2009.01978.x.BooksConceptsProtein kinaseEssential cellular processesTumor suppressor LKB1Downstream AMPK targetsProduction of ATPProtein phosphataseAMPK targetsActivated AMPKIntracellular glycogen accumulationCellular processesUpstream kinaseFatty acid metabolismCardiac myocyte hypertrophyAMPK activationAMPK activityImportant intracellularMolecular mechanismsMajor regulatorAMPKProtein synthesisKinaseAcid metabolismOral hypoglycaemic drugsGlycogen accumulationType 2 diabetes
2008
AMP-Activated Protein Kinase Conducts the Ischemic Stress Response Orchestra
Young LH. AMP-Activated Protein Kinase Conducts the Ischemic Stress Response Orchestra. Circulation 2008, 117: 832-840. PMID: 18268160, DOI: 10.1161/circulationaha.107.713115.BooksMacrophage migration inhibitory factor stimulates AMP-activated protein kinase in the ischaemic heart
Miller EJ, Li J, Leng L, McDonald C, Atsumi T, Bucala R, Young LH. Macrophage migration inhibitory factor stimulates AMP-activated protein kinase in the ischaemic heart. Nature 2008, 451: 578-582. PMID: 18235500, DOI: 10.1038/nature06504.Peer-Reviewed Original ResearchMeSH KeywordsAMP-Activated Protein KinasesAnimalsAntigens, Differentiation, B-LymphocyteCoronary Artery DiseaseEnzyme ActivationGenetic Predisposition to DiseaseGenotypeGlucoseHistocompatibility Antigens Class IIHumansHypoxiaMacrophage Migration-Inhibitory FactorsMiceMultienzyme ComplexesMyocardial IschemiaMyocardial Reperfusion InjuryMyocardiumPolymorphism, GeneticPromoter Regions, GeneticProtein Serine-Threonine KinasesRatsSignal TransductionConceptsIschemic heartMacrophage migration inhibitory factorLower MIF levelsCoronary artery diseaseIschemic heart diseaseMigration inhibitory factorPotential risk markerMIF levelsArtery diseaseRisk markersHeart diseaseIschemic stressCytokine MIFInhibitory factorGlucose uptakePotential drug targetsDiseaseHeartDrug targetsCellular stress responseAMPKMaster regulatorNew studiesPatientsAtherosclerosis
2007
Infusion of a biotinylated bis-glucose photolabel: a new method to quantify cell surface GLUT4 in the intact mouse heart
Miller EJ, Li J, Sinusas KM, Holman GD, Young LH. Infusion of a biotinylated bis-glucose photolabel: a new method to quantify cell surface GLUT4 in the intact mouse heart. AJP Endocrinology And Metabolism 2007, 292: e1922-e1928. PMID: 17341550, DOI: 10.1152/ajpendo.00170.2006.Peer-Reviewed Original ResearchConceptsBio-LCCell surface GLUT4Glucose transporterSurface GLUT4Cell surface glucose transportersGlucose transporter contentCell surface GLUT1Glucose transporter GLUT4Intracellular storage vesiclesMouse heartsTransporter contentSpecific glucose transportersCell surface membraneGlucose uptakeCell surface contentMolecular regulationIntact mouse heartsGLUT4Cell surfaceStorage vesiclesGlucose transportMetabolic stressTransgenic mouse heartsSurface membraneTransporters
2006
Value of peripheral vascular endothelial function in the detection of relative myocardial ischemia in asymptomatic type 2 diabetic patients who underwent myocardial perfusion imaging
Papaioannou GI, Kasapis C, Seip RL, Grey NJ, Katten D, Wackers FJ, Inzucchi SE, Engel S, Taylor A, Young LH, Chyun DA, Davey JA, Iskandrian AE, Ratner RE, Robinson EC, Carolan S, Heller GV. Value of peripheral vascular endothelial function in the detection of relative myocardial ischemia in asymptomatic type 2 diabetic patients who underwent myocardial perfusion imaging. Journal Of Nuclear Cardiology 2006, 13: 362-368. PMID: 16750781, DOI: 10.1016/j.nuclcard.2006.01.022.Peer-Reviewed Original ResearchConceptsEndothelium-dependent vasodilationEndothelium-independent vasodilationCoronary artery diseaseMyocardial perfusion imagingRelative myocardial ischemiaAsymptomatic patientsEndothelial functionNegative predictive valueMyocardial ischemiaAsymptomatic type 2 diabetic patientsExclusion of CADPredictive valueAdenosine myocardial perfusion imagingPeripheral vascular endothelial functionType 2 diabetic patientsType 2 diabetes mellitusHigh negative predictive valueAsymptomatic Diabetics (DIAD) studyBrachial artery ultrasonographyVascular endothelial functionDetection of ischemiaEDV responseRelative ischemiaEndothelial dysfunctionOvert atherosclerosisActivation of AMPK α- and γ-isoform complexes in the intact ischemic rat heart
Li J, Coven DL, Miller EJ, Hu X, Young ME, Carling D, Sinusas AJ, Young LH. Activation of AMPK α- and γ-isoform complexes in the intact ischemic rat heart. AJP Heart And Circulatory Physiology 2006, 291: h1927-h1934. PMID: 16648175, DOI: 10.1152/ajpheart.00251.2006.Peer-Reviewed Original ResearchConceptsAMPK activityAMPK complexAlpha subunit activationDifferent subunit isoformsSerine-threonine kinaseCellular metabolic processesGamma subunit isoformsRegulatory betaAlpha-subunit contentHeterotrimeric complexProtein kinaseAMPK αMultiple isoformsKinase activitySubunit isoformsMetabolic processesAMPK phosphorylationAMPKIsoformsPhysiological regulationKinaseMutationsComplexesKey rolePathophysiological importance
2005
AMP-Activated Protein Kinase: A Key Stress Signaling Pathway in the Heart
Young LH, Li J, Baron SJ, Russell RR. AMP-Activated Protein Kinase: A Key Stress Signaling Pathway in the Heart. Trends In Cardiovascular Medicine 2005, 15: 110-118. PMID: 16039971, DOI: 10.1016/j.tcm.2005.04.005.BooksConceptsLeft ventricular contractile dysfunctionVentricular contractile dysfunctionFatty acid oxidationProtein kinaseCardiovascular actionsHeart failureContractile dysfunctionWolff-ParkinsonWhite syndromeTransgenic miceGlycogen overloadStress Signaling PathwaysImportant regulatory mechanismSignaling pathwaysHeartAcid oxidationGlucose transportMolecular mechanismsAnabolic pathwaysRegulatory mechanismsAMPDual Mechanisms Regulating AMPK Kinase Action in the Ischemic Heart
Baron SJ, Li J, Russell RR, Neumann D, Miller EJ, Tuerk R, Wallimann T, Hurley RL, Witters LA, Young LH. Dual Mechanisms Regulating AMPK Kinase Action in the Ischemic Heart. Circulation Research 2005, 96: 337-345. PMID: 15653571, DOI: 10.1161/01.res.0000155723.53868.d2.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine MonophosphateAdenosine TriphosphateAminoimidazole CarboxamideAMP-Activated Protein Kinase KinasesAMP-Activated Protein KinasesAnimalsInfusions, IntravenousMaleMultienzyme ComplexesMyocardial IschemiaMyocardiumPhosphorylationProtein KinasesProtein Serine-Threonine KinasesRatsRats, Sprague-DawleyRecombinant ProteinsRibonucleotidesConceptsRecombinant AMPKAMPKK activityAMPK phosphorylationPhosphorylation of Thr172Gamma regulatory subunitsIschemic heartImportant signaling proteinAlpha catalytic subunitRat heartHeterotrimeric AMPKAMPKKHeterotrimeric complexActivation loopRegulatory subunitKinase actionSignaling proteinsCatalytic subunitProtein kinaseAMPK activityLow-flow ischemiaGamma subunitsAMPKInteraction of AMPPhosphorylationAddition of AMP
2004
Cardiac myocyte‐specific HIF‐1α deletion alters vascularization, energy availability, calcium flux, and contractility in the normoxic heart
Huang Y, Hickey RP, Yeh JL, Liu D, Dadak A, Young LH, Johnson RS, Giordano FJ. Cardiac myocyte‐specific HIF‐1α deletion alters vascularization, energy availability, calcium flux, and contractility in the normoxic heart. The FASEB Journal 2004, 18: 1138-1140. PMID: 15132980, DOI: 10.1096/fj.04-1510fje.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCalcium SignalingCoronary CirculationDNA-Binding ProteinsEnergy MetabolismGene DeletionGene Expression RegulationHeart Function TestsHypoxia-Inducible Factor 1Hypoxia-Inducible Factor 1, alpha SubunitMiceMice, Inbred C57BLMice, KnockoutMyocardial ContractionMyocardiumMyocytes, CardiacNeovascularization, PhysiologicNuclear ProteinsOxygen ConsumptionReverse Transcriptase Polymerase Chain ReactionRNA, MessengerTranscription FactorsTranscription, GeneticConceptsCardiac functionCalcium fluxHypoxia-inducible transcription factor HIF-1alphaCardiac oxygen deliveryDisease statesHIF-1alphaSkeletal muscleCardiac contractile dysfunctionHigh-energy phosphate contentCardiovascular disease statesResting pulse rateTranscription factor HIF-1alphaCoronary vasodilatationMyocardial demandContractile dysfunctionMyocardial hibernationNormoxic heartsOxygen supplyGene expressionCalcium handlingOxygen deliveryPulse rateHeart muscleCardiac muscleMolecular pathology
2003
Insulin resistance and the effects of thiazolidinediones on cardiac metabolism
Young LH. Insulin resistance and the effects of thiazolidinediones on cardiac metabolism. The American Journal Of Medicine 2003, 115: 75-80. PMID: 14678870, DOI: 10.1016/j.amjmed.2003.09.013.BooksConceptsMyocardial metabolismFree fatty acidsAdministration of thiazolidinedionesImproved glucose metabolismEffects of thiazolidinedionesInsulin-sensitizing effectsRecovery of functionCardiac contractile activityPotential beneficial effectsPostischemic periodDiabetes mellitusMyocardial injuryFFA metabolismInsulin resistanceFatty acid concentrationsContractile activityGlucose metabolismAnimal studiesCardiac metabolismPharmacologic manipulationThiazolidinedionesBeneficial effectsSkeletal muscleHigh rateMetabolismPhysiological role of AMP-activated protein kinase in the heart: graded activation during exercise
Coven DL, Hu X, Cong L, Bergeron R, Shulman GI, Hardie DG, Young LH. Physiological role of AMP-activated protein kinase in the heart: graded activation during exercise. AJP Endocrinology And Metabolism 2003, 285: e629-e636. PMID: 12759223, DOI: 10.1152/ajpendo.00171.2003.Peer-Reviewed Original ResearchConceptsAMPK activityProtein kinasePhysiological roleTotal AMPK activityAlpha2 catalytic subunitCellular metabolic processesAlpha catalytic subunitCardiac AMPK activityAMPK effectsAMPK activationMetabolic processesAMPKAkt phosphorylationKinasePhosphorylationSkeletal muscleSubunitsSubstrate metabolismActivationActivity increasesLesser extentMyocardial substrate metabolismMin of treadmillHigh-intensity exerciseActivity
2000
Effect of hyperinsulinemia on myocardial amino acid uptake in patients with coronary artery disease
McNulty P, Jacob R, Deckelbaum L, Young L. Effect of hyperinsulinemia on myocardial amino acid uptake in patients with coronary artery disease. Metabolism 2000, 49: 1365-1369. PMID: 11079831, DOI: 10.1053/meta.2000.9510.Peer-Reviewed Original ResearchConceptsBranched-chain amino acidsIschemic heart diseaseMyocardial uptakeArterial plasmaHeart diseaseChronic ischemic heart diseaseCoronary artery diseasePlasma BCAA concentrationsEffect of hyperinsulinemiaMyocardial glucose uptakeNet myocardial uptakeEuglycemic insulin infusionsNet glutamate uptakeOxidative energy substratesPossible salutary effectsBCAA uptakeMyocardial utilizationEuglycemic hyperinsulinemiaArtery diseaseInsulin levelsBCAA concentrationsInsulin infusionAmino acid uptakeAnabolic effectsCardiovascular diseaseCellular and molecular regulation of cardiac glucose transport
Young L, Coven D, Russell R. Cellular and molecular regulation of cardiac glucose transport. Journal Of Nuclear Cardiology 2000, 7: 267-276. PMID: 10888399, DOI: 10.1016/s1071-3581(00)70016-x.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus Statements
1999
Translocation of myocardial GLUT-4 and increased glucose uptake through activation of AMPK by AICAR
Russell R, Bergeron R, Shulman G, Young L. Translocation of myocardial GLUT-4 and increased glucose uptake through activation of AMPK by AICAR. American Journal Of Physiology 1999, 277: h643-h649. PMID: 10444490, DOI: 10.1152/ajpheart.1999.277.2.h643.Peer-Reviewed Original ResearchMeSH KeywordsAminoimidazole CarboxamideAMP-Activated Protein KinasesAnimalsBiological TransportEnzyme ActivationGlucoseGlucose Transporter Type 4In Vitro TechniquesMaleMonosaccharide Transport ProteinsMultienzyme ComplexesMuscle ProteinsMyocardiumProtein Serine-Threonine KinasesRatsRats, Sprague-DawleyRibonucleotidesSarcolemmaConceptsAMPK activationGLUT-4 translocationGLUT-4Glucose uptakeProtein kinase activityActivator of AMPKActivation of AMPKInsulin-stimulated increasePI3K-independent pathwayInsulin-stimulated glucose uptakePI3K inhibitorsKinase activityAICARDeoxyglucose uptakeAMPKTranslocationIschemia-induced translocationK inhibitorsAdenine 9Myocyte sarcolemmaPathwayImmunofluorescence studiesMuscle glucose uptakeActivationCardiac myocytes