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
2014
The vestigial enzyme D-dopachrome tautomerase protects the heart against ischemic injury
Qi D, Atsina K, Qu L, Hu X, Wu X, Xu B, Piecychna M, Leng L, Fingerle-Rowson G, Zhang J, Bucala R, Young LH. The vestigial enzyme D-dopachrome tautomerase protects the heart against ischemic injury. Journal Of Clinical Investigation 2014, 124: 3540-3550. PMID: 24983315, PMCID: PMC4109524, DOI: 10.1172/jci73061.Peer-Reviewed Original ResearchConceptsMacrophage migration inhibitory factorContractile dysfunctionAntibody-dependent neutralizationAutocrine/paracrine effectsCoronary artery ligationCardiac contractile dysfunctionMigration inhibitory factorLV contractile dysfunctionDopachrome tautomeraseMolecular signaling pathwaysArtery ligationIschemic injuryCardiac sizeCardiomyocyte secretionControl heartsProtective effectKnockout miceParacrine effectsIschemic stressPhysiologic responsesInhibitory factorMore necrosisDysfunctionInjuryMurine cardiomyocytes
2013
NO triggers RGS4 degradation to coordinate angiogenesis and cardiomyocyte growth
Jaba IM, Zhuang ZW, Li N, Jiang Y, Martin KA, Sinusas AJ, Papademetris X, Simons M, Sessa WC, Young LH, Tirziu D. NO triggers RGS4 degradation to coordinate angiogenesis and cardiomyocyte growth. Journal Of Clinical Investigation 2013, 123: 1718-1731. PMID: 23454748, PMCID: PMC3613910, DOI: 10.1172/jci65112.Peer-Reviewed Original ResearchMeSH KeywordsAdaptation, BiologicalAnimalsCell EnlargementCells, CulturedCoronary VesselsEndothelium, VascularHeart VentriclesMechanistic Target of Rapamycin Complex 1MiceMice, Inbred C57BLMice, TransgenicMultiprotein ComplexesMyocytes, CardiacNeovascularization, PhysiologicNG-Nitroarginine Methyl EsterNitric OxideNitric Oxide SynthasePlacenta Growth FactorPregnancy ProteinsProteinsProteolysisProto-Oncogene Proteins c-aktRatsRats, Sprague-DawleyRGS ProteinsSignal TransductionTOR Serine-Threonine KinasesConceptsCardiomyocyte growthAkt/mTORC1 signalingNovel NO-dependent mechanismProteasomal degradationCoordination of angiogenesisMTORC1 signalingConditional overexpressionMurine cardiac tissueG proteinsTransgenic expressionAkt/Physiological mechanismsMyocyte growthVessel growthGrowth factorTransgenic miceHypertrophic responseAngiogenesisKnockout miceMyocardial hypertrophyExpressionGrowthCardiac hypertrophyNOS inhibitor L-NAMEInduction
2012
Cerulein hyperstimulation decreases AMP-activated protein kinase levels at the site of maximal zymogen activation
Shugrue C, Alexandre M, de Villalvilla A, Kolodecik TR, Young LH, Gorelick FS, Thrower EC. Cerulein hyperstimulation decreases AMP-activated protein kinase levels at the site of maximal zymogen activation. AJP Gastrointestinal And Liver Physiology 2012, 303: g723-g732. PMID: 22821946, PMCID: PMC3468535, DOI: 10.1152/ajpgi.00082.2012.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAminoimidazole CarboxamideAMP-Activated Protein KinasesAnimalsCells, CulturedCeruletideCyclic AMP-Dependent Protein KinasesEnzyme PrecursorsGene Expression RegulationMaleMetforminOctoxynolPancreasPhosphorylationPyrazolesPyrimidinesRatsRats, Sprague-DawleyRibonucleotidesSodium Dodecyl SulfateConceptsAdenosine monophosphate-activated protein kinaseZymogen activationAMPK activityPancreatic acinar cellsMonophosphate-activated protein kinaseVacuolar ATPase activityAMPK levelsDigestive enzyme zymogensAMPK effectsProtein kinaseProtein kinase levelsE subunitAcinar cellsTime-dependent translocationCompound CCellular modelPancreatitis responsesATPase activityDifferential centrifugationPremature activationChymotrypsin activityActivationInitiating eventSoluble fractionCerulein hyperstimulation
2008
Macrophage 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
Aging-Associated Reductions in AMP-Activated Protein Kinase Activity and Mitochondrial Biogenesis
Reznick RM, Zong H, Li J, Morino K, Moore IK, Yu HJ, Liu ZX, Dong J, Mustard KJ, Hawley SA, Befroy D, Pypaert M, Hardie DG, Young LH, Shulman GI. Aging-Associated Reductions in AMP-Activated Protein Kinase Activity and Mitochondrial Biogenesis. Cell Metabolism 2007, 5: 151-156. PMID: 17276357, PMCID: PMC1885964, DOI: 10.1016/j.cmet.2007.01.008.Peer-Reviewed Original ResearchConceptsIntracellular lipid metabolismMitochondrial biogenesisAMPK activityMitochondrial functionProtein kinase activityLipid metabolismProtein kinaseKinase activityAge-associated reductionBiogenesisOld ratsAMPKSkeletal muscleRecent studiesInsulin resistanceChronic activationMetabolismAcute stimulationFat oxidationImportant roleAcid feedingKinaseRatsActivityRegulation
2006
Activation 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 Activates p38 Mitogen-Activated Protein Kinase by Increasing Recruitment of p38 MAPK to TAB1 in the Ischemic Heart
Li J, Miller EJ, Ninomiya-Tsuji J, Russell RR, Young LH. AMP-Activated Protein Kinase Activates p38 Mitogen-Activated Protein Kinase by Increasing Recruitment of p38 MAPK to TAB1 in the Ischemic Heart. Circulation Research 2005, 97: 872-879. PMID: 16179588, DOI: 10.1161/01.res.0000187458.77026.10.Peer-Reviewed Original ResearchMeSH KeywordsAminoimidazole CarboxamideAMP-Activated Protein KinasesAnimalsAnisomycinCell HypoxiaEnzyme ActivationGlucoseGlucose Transporter Type 4Intracellular Signaling Peptides and ProteinsMaleMAP Kinase Kinase 3MiceMice, Inbred C57BLMice, TransgenicMultienzyme ComplexesMyocardial IschemiaP38 Mitogen-Activated Protein KinasesProtein Serine-Threonine KinasesProtein TransportRatsRats, Sprague-DawleyRibonucleotidesConceptsMitogen-activated protein kinaseP38 mitogen-activated protein kinaseMAPK kinase 3P38 MAPK activationAlpha2 catalytic subunitProtein kinaseMAPK activationCatalytic subunitGlucose transportStress-signaling pathwaysAMPK activator 5Role of AMPKProtein kinase 1Direct molecular targetP38 MAPK inhibitorMouse heartsAMPK complexProtein TAB1Scaffold proteinGLUT4 translocationUpstream kinaseAMPK activationKinase 3Kinase 1MAPK inhibitorDual 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
Role of the nitric oxide pathway in AMPK-mediated glucose uptake and GLUT4 translocation in heart muscle
Li J, Hu X, Selvakumar P, Russell RR, Cushman SW, Holman GD, Young LH. Role of the nitric oxide pathway in AMPK-mediated glucose uptake and GLUT4 translocation in heart muscle. AJP Endocrinology And Metabolism 2004, 287: e834-e841. PMID: 15265762, DOI: 10.1152/ajpendo.00234.2004.Peer-Reviewed Original ResearchMeSH KeywordsAminoimidazole CarboxamideAMP-Activated Protein KinasesAnimalsBiological TransportEnzyme ActivationGlucoseGlucose Transporter Type 4Hypoglycemic AgentsIn Vitro TechniquesMaleMonosaccharide Transport ProteinsMultienzyme ComplexesMuscle ProteinsNitric OxideNitric Oxide SynthaseNitric Oxide Synthase Type IIIPapillary MusclesProtein Serine-Threonine KinasesProtein TransportRatsRats, Sprague-DawleyRibonucleotidesConceptsGLUT4 translocationAMPK stimulationGlucose transportAMPK catalytic subunitGlucose uptakeCell surfaceGlucose transporter GLUT4Serine-threonine kinaseEndothelial NO synthasePotential downstream mediatorsVesicular traffickingCatalytic subunitProtein kinaseAICAR treatmentCellular metabolismNitric oxide pathwayAMPKDownstream mediatorTranslocationEssential roleHeart muscleOxide pathwayCyclase pathwayPathwayAICAR
2003
Physiological 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
2001
Chronic activation of AMP kinase results in NRF-1 activation and mitochondrial biogenesis
Bergeron R, Ren J, Cadman K, Moore I, Perret P, Pypaert M, Young L, Semenkovich C, Shulman G. Chronic activation of AMP kinase results in NRF-1 activation and mitochondrial biogenesis. AJP Endocrinology And Metabolism 2001, 281: e1340-e1346. PMID: 11701451, DOI: 10.1152/ajpendo.2001.281.6.e1340.Peer-Reviewed Original ResearchMeSH Keywords5-Aminolevulinate SynthetaseAdenylate KinaseAnimalsBlotting, NorthernCell NucleusCytochrome c GroupDNA-Binding ProteinsEnergy MetabolismEnzyme ActivationMaleMicroscopy, ElectronMitochondria, MuscleMuscle, SkeletalNF-E2-Related Factor 1Nuclear Respiratory Factor 1Nuclear Respiratory FactorsRatsRats, Sprague-DawleyRNA, MessengerTrans-ActivatorsEffect of 5-Aminoimidazole-4-Carboxamide-1-β-d-Ribofuranoside Infusion on In Vivo Glucose and Lipid Metabolism in Lean and Obese Zucker Rats
Bergeron R, Previs S, Cline G, Perret P, Russell III R, Young L, Shulman G. Effect of 5-Aminoimidazole-4-Carboxamide-1-β-d-Ribofuranoside Infusion on In Vivo Glucose and Lipid Metabolism in Lean and Obese Zucker Rats. Diabetes 2001, 50: 1076-1082. PMID: 11334411, DOI: 10.2337/diabetes.50.5.1076.Peer-Reviewed Original ResearchMeSH KeywordsAdenylate KinaseAminoimidazole CarboxamideAnimalsBlood GlucoseBody WeightFatty Acids, NonesterifiedGlucoseGlycerolInfusions, IntravenousInjections, IntravenousInsulinInsulin ResistanceLactatesMaleModels, AnimalMuscle, SkeletalObesityRatsRats, ZuckerReference ValuesRibonucleotidesTriglyceridesConceptsWhole-body glucose disposalInsulin-resistant rat modelObese ratsEndogenous glucose productionObese Zucker ratsRed gastrocnemius muscleInsulin infusion rateLean ratsGlucose disposalInsulin infusionRat modelInfusion rateGastrocnemius muscleZucker ratsLipid metabolismGlucose productionEndogenous glucose production rateGlucose transport activitySkeletal muscle glucose transport activityType 2 diabetesWhole-body carbohydrateInsulin-stimulated glucose uptakeInsulin-independent pathwaySkeletal muscle AMPKGlucose production rate
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 myocytesEffect of AMPK activation on muscle glucose metabolism in conscious rats
Bergeron R, Russell R, Young L, Ren J, Marcucci M, Lee A, Shulman G. Effect of AMPK activation on muscle glucose metabolism in conscious rats. American Journal Of Physiology 1999, 276: e938-e944. PMID: 10329989, DOI: 10.1152/ajpendo.1999.276.5.e938.Peer-Reviewed Original ResearchMeSH KeywordsAminoimidazole CarboxamideAMP-Activated Protein KinasesAndrostadienesAnimalsBiological TransportDeoxyglucoseElectric StimulationEnzyme ActivationEnzyme InhibitorsIn Vitro TechniquesInsulinMaleMultienzyme ComplexesMuscle ContractionMuscle, SkeletalPhosphatidylinositol 3-KinasesProtein Serine-Threonine KinasesRatsRats, Sprague-DawleyRibonucleotidesTritiumWortmanninConceptsMuscle glucose metabolismGlucose transport activityActivation of AMPKGlucose uptakeGlucose metabolismTransport activitySkeletal muscle glucose metabolismExercise-induced increaseSkeletal muscle glucose transport activityBasal rateAbsence of wortmanninAdenosine receptor antagonistAdditive effectProtein kinase activationVariable infusionConscious ratsReceptor antagonistSaline infusionAwake ratsMedial gastrocnemiusElectrical stimulationEpitrochlearis musclesCellular pathwaysAMPK activationKinase activationInsulin-like growth factor I stimulates cardiac myosin heavy chain and actin synthesis in the awake rat
Young L, Renfu Y, Hu X, Chong S, Hasan S, Jacob R, Sherwin R. Insulin-like growth factor I stimulates cardiac myosin heavy chain and actin synthesis in the awake rat. American Journal Of Physiology 1999, 276: e143-e150. PMID: 9886960, DOI: 10.1152/ajpendo.1999.276.1.e143.Peer-Reviewed Original ResearchConceptsInsulin-like growth factor IGrowth factor IAwake ratsMyosin heavy chainFactor IContractile protein synthesisIGF-I infusionLow-dose IGFMixed cardiac proteinsCardiac myosin heavy chainMyosin synthesisBlood pressureOvernight fastIntravenous infusionRight ventricleHeavy chainHeart rateHypoglycemic effectFed ratsIGFRatsDirect actionProtein synthesisSalineCardiac proteins
1996
IGF-I stimulation of muscle protein synthesis in the awake rat: permissive role of insulin and amino acids
Jacob R, Hu X, Niederstock D, Hasan S, McNulty PH, Sherwin RS, Young LH. IGF-I stimulation of muscle protein synthesis in the awake rat: permissive role of insulin and amino acids. American Journal Of Physiology 1996, 270: e60-e66. PMID: 8772474, DOI: 10.1152/ajpendo.1996.270.1.e60.Peer-Reviewed Original ResearchConceptsMuscle protein synthesisInsulin replacementPlasma insulinAwake ratsInsulin-like growth factor ICapacity of IGFIGF-I infusionInfusion of IGFAction of IGFSaline control valuesGrowth factor IIGF-I stimulationProtein synthesisIntravenous infusionPlasma concentrationsInsulin concentrationsAmino acid concentrationsIGFPermissive roleInfusionFactor IControl valuesInsulinRatsAmino acids
1994
Effect of insulin on rat heart and skeletal muscle phenylalanyl-tRNA labeling and protein synthesis in vivo
Young LH, Stirewalt W, McNulty PH, Revkin JH, Barrett EJ. Effect of insulin on rat heart and skeletal muscle phenylalanyl-tRNA labeling and protein synthesis in vivo. American Journal Of Physiology 1994, 267: e337-e342. PMID: 8074214, DOI: 10.1152/ajpendo.1994.267.2.e337.Peer-Reviewed Original ResearchConceptsMuscle protein synthesisAcid-soluble poolFemoral venous plasmaSkeletal muscleSkeletal muscle protein synthesisEffect of insulinMuscle protein hydrolysateProtein synthesisContinuous infusionVenous plasmaHyperinsulinemic clampSaline infusionAnesthetized ratsArterial plasmaRat heartInsulin effectInsulinHormonal regulationHeartInfusionMuscleSpecific activityMinVivo measurementsLabeling
1993
Response of rat heart and skeletal muscle protein in vivo to insulin and amino acid infusion
McNulty PH, Young LH, Barrett EJ. Response of rat heart and skeletal muscle protein in vivo to insulin and amino acid infusion. American Journal Of Physiology 1993, 264: e958-e965. PMID: 8333520, DOI: 10.1152/ajpendo.1993.264.6.e958.Peer-Reviewed Original ResearchConceptsAmino acid infusionMuscle protein synthesisContinuous infusionAcid infusionNet muscle protein synthesisSaline-treated ratsSkeletal muscle protein synthesisInfusion of insulinPlasma specific activitySkeletal muscle proteinsProtein synthesisAmino acid solutionMature ratsInfusionRat heartInsulinBolusTracer infusionHeart muscleSkeletal muscleTracer infusion methodRatsPhysiological concentrationsAmino acidsProtein synthesis in pulmonary arteries from rats exposed to hyperoxia
Stirewalt WS, Coflesky JT, Young LH, Evans JN. Protein synthesis in pulmonary arteries from rats exposed to hyperoxia. American Journal Of Physiology 1993, 264: l74-l79. PMID: 8430819, DOI: 10.1152/ajplung.1993.264.1.l74.Peer-Reviewed Original Research