2024
A Concept of “Athero-Oncology”: Tumor-Like Smooth Muscle Cells Drive Atherosclerosis
Chatterjee P, Martin K. A Concept of “Athero-Oncology”: Tumor-Like Smooth Muscle Cells Drive Atherosclerosis. Circulation 2024, 149: 1899-1902. PMID: 38857330, DOI: 10.1161/circulationaha.124.069446.Peer-Reviewed Original Research
2023
Role of ascorbic acid in cardiac allograft vasculopathy
Chang A, Martin K, Colvin M, Bellumkonda L. Role of ascorbic acid in cardiac allograft vasculopathy. Clinical Transplantation 2023, 37: e15153. PMID: 37792313, DOI: 10.1111/ctr.15153.Peer-Reviewed Original ResearchConceptsCardiac allograft vasculopathySmooth muscle cell apoptosisAllograft vasculopathyDisease processMuscle cell apoptosisSignificant long-term morbidityCell apoptosisProgressive fibroproliferative diseasePost-transplant carePost-transplant managementLong-term morbiditySmall clinical trialsChallenging disease processVascular smooth muscle cell apoptosisHeart transplantationCAV progressionEndothelial dysfunctionRapamycin inhibitorsClinical trialsIntimal thickeningPrevents developmentInterferon γRodent modelsIntimal hyperplasiaMTOR inhibitorsTNFα increases the degradation of pyruvate dehydrogenase kinase 4 by the Lon protease to support proinflammatory genes
Boutagy N, Fowler J, Grabinska K, Cardone R, Sun Q, Vazquez K, Whalen M, Zhu X, Chakraborty R, Martin K, Simons M, Romanoski C, Kibbey R, Sessa W. TNFα increases the degradation of pyruvate dehydrogenase kinase 4 by the Lon protease to support proinflammatory genes. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2218150120. PMID: 37695914, PMCID: PMC10515159, DOI: 10.1073/pnas.2218150120.Peer-Reviewed Original ResearchConceptsPyruvate dehydrogenase kinase 4Dehydrogenase kinase 4Lon proteasePyruvate dehydrogenase activityHistone acetylationMitochondrial metabolismKinase 4Specific gene lociPDH fluxEndothelial cellsSiRNA-mediated knockdownAcetyl-CoA generationLysine 27Gene transcriptionTCA fluxRNA sequencingHuman umbilical vein endothelial cellsProtein degradationHistone 3Gene locusUmbilical vein endothelial cellsNF-κB-dependent mechanismTricarboxylic acid cycle fluxVein endothelial cellsActive subunitSex hormones impact early maturation and immune response in the arteriovenous fistula mouse model
Satam K, Ohashi Y, Thaxton C, Gonzalez L, Setia O, Bai H, Aoyagi Y, Xie Y, Zhang W, Yatsula B, Martin K, Cai Y, Dardik A. Sex hormones impact early maturation and immune response in the arteriovenous fistula mouse model. AJP Heart And Circulatory Physiology 2023, 325: h77-h88. PMID: 37145957, PMCID: PMC10243550, DOI: 10.1152/ajpheart.00049.2023.Peer-Reviewed Original ResearchConceptsIntact female miceAVF maturationSex hormonesT cellsFemale miceArteriovenous fistulaMale miceMouse modelHigher IL-10Arteriovenous fistula creationImmune cell recruitmentSex-specific therapiesHormone receptor signalingSex differencesHuman AVF maturationAVF surgeryMale patientsClinical outcomesFemale patientsFistula maturationIL-10C57BL/6 miceInferior outcomesVenous adaptationFistula creationThe age of bone marrow dictates the clonality of smooth muscle-derived cells in atherosclerotic plaques
Kabir I, Zhang X, Dave J, Chakraborty R, Qu R, Chandran R, Ntokou A, Gallardo-Vara E, Aryal B, Rotllan N, Garcia-Milian R, Hwa J, Kluger Y, Martin K, Fernández-Hernando C, Greif D. The age of bone marrow dictates the clonality of smooth muscle-derived cells in atherosclerotic plaques. Nature Aging 2023, 3: 64-81. PMID: 36743663, PMCID: PMC9894379, DOI: 10.1038/s43587-022-00342-5.Peer-Reviewed Original ResearchConceptsAtherosclerotic plaquesBone marrowSmooth muscle-derived cellsSMC progenitorsAtherosclerotic plaque cellsSmooth muscle cell progenitorsPredominant risk factorCause of deathNovel therapeutic strategiesTNF receptor 1Muscle-derived cellsAged bone marrowAged BMEffect of agePlaque burdenAged miceRisk factorsTumor necrosisTherapeutic strategiesPlaque cellsMyeloid cellsReceptor 1Integrin β3Cell progenitorsAtherosclerosis
2021
TET2 Protects Against Vascular Smooth Muscle Cell Apoptosis and Intimal Thickening in Transplant Vasculopathy
Ostriker AC, Xie Y, Chakraborty R, Sizer AJ, Bai Y, Ding M, Song WL, Huttner A, Hwa J, Martin KA. TET2 Protects Against Vascular Smooth Muscle Cell Apoptosis and Intimal Thickening in Transplant Vasculopathy. Circulation 2021, 144: 455-470. PMID: 34111946, PMCID: PMC8643133, DOI: 10.1161/circulationaha.120.050553.Peer-Reviewed Original ResearchMeSH KeywordsAllograftsAnimalsApoptosisBiomarkersDioxygenasesDisease Models, AnimalDisease SusceptibilityDNA-Binding ProteinsHeart TransplantationHumansImmunohistochemistryInterferon-gammaMiceMice, KnockoutMyocytes, Smooth MuscleSignal TransductionSTAT1 Transcription FactorTunica IntimaVascular DiseasesConceptsCoronary allograft vasculopathyGraft arteriopathyIntimal thickeningCAV progressionRole of TET2VSMC apoptosisTransplant samplesGraft modelHigh-dose ascorbic acidTET2 expressionVSMC phenotypeContext of transplantCoronary blood flowEffect of IFNγTET2 activityTET2 depletionSmooth muscle cell apoptosisVascular smooth muscle cell apoptosisMuscle cell apoptosisAllograft vasculopathyDevastating sequelaeMedial thinningAortic graftHeart transplantTransplant failure
2020
Thrombocytopathy and endotheliopathy: crucial contributors to COVID-19 thromboinflammation
Gu SX, Tyagi T, Jain K, Gu VW, Lee SH, Hwa JM, Kwan JM, Krause DS, Lee AI, Halene S, Martin KA, Chun HJ, Hwa J. Thrombocytopathy and endotheliopathy: crucial contributors to COVID-19 thromboinflammation. Nature Reviews Cardiology 2020, 18: 194-209. PMID: 33214651, PMCID: PMC7675396, DOI: 10.1038/s41569-020-00469-1.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsMeSH KeywordsAdministration, InhalationAnticoagulantsBlood Coagulation DisordersBlood Platelet DisordersCOVID-19COVID-19 Drug TreatmentEndothelium, VascularEndothelium-Dependent Relaxing FactorsEpoprostenolHeart Disease Risk FactorsHumansIloprostInflammationNitric OxidePlatelet Aggregation InhibitorsSARS-CoV-2Systemic Inflammatory Response SyndromeThrombosisThrombotic MicroangiopathiesVascular DiseasesVasodilator AgentsVenous ThromboembolismConceptsCardiovascular risk factorsRisk factorsCOVID-19Severe acute respiratory syndrome coronavirus 2Pre-existing cardiovascular diseaseAcute respiratory syndrome coronavirus 2Traditional cardiovascular risk factorsAcute respiratory distress syndromeRespiratory syndrome coronavirus 2Respiratory distress syndromeManagement of patientsSyndrome coronavirus 2COVID-19 pathologyCoronavirus disease 2019Potential therapeutic strategyCytokine stormEndothelial dysfunctionThrombotic complicationsDistress syndromeExcessive inflammationCoronavirus 2Severe outcomesAdvanced ageCardiovascular diseaseDisease 2019Circular RNA CircMAP3K5 Acts as a MicroRNA-22-3p Sponge to Promote Resolution of Intimal Hyperplasia Via TET2-Mediated Smooth Muscle Cell Differentiation
Zeng Z, Xia L, Fan S, Zheng J, Qin J, Fan X, Liu Y, Tao J, Liu Y, Li K, Ling Z, Bu Y, Martin KA, Hwa J, Liu R, Tang WH. Circular RNA CircMAP3K5 Acts as a MicroRNA-22-3p Sponge to Promote Resolution of Intimal Hyperplasia Via TET2-Mediated Smooth Muscle Cell Differentiation. Circulation 2020, 143: 354-371. PMID: 33207953, DOI: 10.1161/circulationaha.120.049715.Peer-Reviewed Original ResearchConceptsHuman coronary artery smooth muscle cellsTet2 knockout miceCoronary artery smooth muscle cellsArtery smooth muscle cellsCircular RNAsSmooth muscle cellsVascular smooth muscle cellsWire-injured mouse femoral arteriesSmooth muscle cell differentiationCircular RNA profilingMuscle cell differentiationRNA sequencing dataLoss of TET2Coronary heart diseaseVascular SMC differentiationMiR-22-3pPlatelet-derived growth factorKnockout miceSMC differentiationMaster regulatorRNA sequencingRNA profilingPlatelet-derived growth factor-BBGene expressionSequencing data
2019
Promoters to Study Vascular Smooth Muscle
Chakraborty R, Saddouk FZ, Carrao AC, Krause DS, Greif DM, Martin KA. Promoters to Study Vascular Smooth Muscle. Arteriosclerosis Thrombosis And Vascular Biology 2019, 39: 603-612. PMID: 30727757, PMCID: PMC6527360, DOI: 10.1161/atvbaha.119.312449.Peer-Reviewed Original ResearchMeSH KeywordsActinsAnimalsCell LineCell LineageCell TransdifferentiationGene Expression RegulationGene Knockout TechniquesGene TargetingHumansMiceMicrofilament ProteinsMuscle ProteinsMuscle, Smooth, VascularMyocytes, Smooth MuscleMyofibroblastsMyosin Heavy ChainsNeovascularization, PathologicNeovascularization, PhysiologicPhenotypePromoter Regions, GeneticRecombinant Fusion ProteinsConceptsSmooth muscle cellsCre driver linesDiversity of phenotypesMuscle cell typesVisceral smooth muscle cellsSMC transdifferentiationActa2 promoterRemarkable plasticityExciting new eraSMC functionCell typesCre linesEmbryonic heartExciting discoveriesPhenotypeMuscle cellsPerivascular adipocytesPromoterVascular smooth muscleNonmuscular cellsExpressionMyeloid cellsCardiovascular phenotypesCellsBlood vessel wall
2017
Opposing Actions of AKT (Protein Kinase B) Isoforms in Vascular Smooth Muscle Injury and Therapeutic Response
Jin Y, Xie Y, Ostriker AC, Zhang X, Liu R, Lee MY, Leslie KL, Tang W, Du J, Lee SH, Wang Y, Sessa WC, Hwa J, Yu J, Martin KA. Opposing Actions of AKT (Protein Kinase B) Isoforms in Vascular Smooth Muscle Injury and Therapeutic Response. Arteriosclerosis Thrombosis And Vascular Biology 2017, 37: 2311-2321. PMID: 29025710, PMCID: PMC5699966, DOI: 10.1161/atvbaha.117.310053.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBinding SitesCell Cycle ProteinsCell DifferentiationCell MovementCell ProliferationCells, CulturedDisease Models, AnimalForkhead Transcription FactorsGene Expression RegulationGenetic Predisposition to DiseaseHumansMice, KnockoutMuscle, Smooth, VascularMyocytes, Smooth MuscleNeointimaNuclear ProteinsPhenotypePromoter Regions, GeneticProto-Oncogene Proteins c-aktRNA InterferenceRNA, MessengerSignal TransductionSirolimusTime FactorsTrans-ActivatorsTranscription FactorsTransfectionVascular System InjuriesConceptsIntimal hyperplasiaTherapeutic inhibitionVascular smooth muscle injurySmooth muscle-specific deletionSmooth muscle cell proliferationSystemic vascular diseaseSevere intimal hyperplasiaSmooth muscle injuryNew treatment strategiesWild-type miceAkt isoformsMuscle cell proliferationMuscle-specific deletionMechanism of actionVascular smooth muscle cell differentiationCoronary revascularizationSmooth muscle cell differentiationDiabetes mellitusDiabetic patientsControl miceRapamycin therapyVascular diseaseMuscle injuryTherapeutic responseSevere thrombosis
2015
Phosphorylation of GATA-6 is required for vascular smooth muscle cell differentiation after mTORC1 inhibition
Xie Y, Jin Y, Merenick BL, Ding M, Fetalvero KM, Wagner RJ, Mai A, Gleim S, Tucker DF, Birnbaum MJ, Ballif BA, Luciano AK, Sessa WC, Rzucidlo EM, Powell RJ, Hou L, Zhao H, Hwa J, Yu J, Martin KA. Phosphorylation of GATA-6 is required for vascular smooth muscle cell differentiation after mTORC1 inhibition. Science Signaling 2015, 8: ra44. PMID: 25969542, PMCID: PMC4560350, DOI: 10.1126/scisignal.2005482.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell DifferentiationCell ProliferationGATA6 Transcription FactorHEK293 CellsHumansMechanistic Target of Rapamycin Complex 1MiceMice, KnockoutMultiprotein ComplexesMuscle ProteinsMuscle, Smooth, VascularMyocytes, Smooth MuscleProto-Oncogene Proteins c-aktTOR Serine-Threonine KinasesConceptsGATA-6Vascular smooth muscle cell differentiationSmooth muscle cell differentiationPhosphorylation-deficient mutantDifferentiation of VSMCsRapamycin complex 1Downstream transcriptional targetsTranscription factor GATA-6Muscle cell differentiationInhibition of mTORC1VSMC hyperplasiaTransactivation of promotersTranscriptional targetsVSMC differentiationNuclear accumulationInduced phosphorylationMechanistic targetReversible differentiationCell differentiationCells undergoDrug targetsInhibition of proliferationPhosphorylationWild-type miceMTORC1
2014
Epigenetic regulation of smooth muscle cell plasticity
Liu R, Leslie KL, Martin KA. Epigenetic regulation of smooth muscle cell plasticity. Biochimica Et Biophysica Acta 2014, 1849: 448-453. PMID: 24937434, PMCID: PMC4552189, DOI: 10.1016/j.bbagrm.2014.06.004.Peer-Reviewed Original ResearchConceptsSMC plasticityEpigenetic regulationSmooth muscle cellsCell plasticitySmooth Muscle Cell PlasticityRegulatory cis elementsCell typesDNA demethylation pathwayLevel of epigeneticsMuscle cell plasticityMature cell typesKey transcription factorMajor cell typesHistone modificationsNovel target moleculesDNA methylationTranscription factorsEnvironmental stressCis elementsPhenotypic statesDemethylation pathwaySMC phenotypeMolecular mechanismsAdult bodyRemarkable plasticity
2013
Ten-Eleven Translocation-2 (TET2) Is a Master Regulator of Smooth Muscle Cell Plasticity
Liu R, Jin Y, Tang WH, Qin L, Zhang X, Tellides G, Hwa J, Yu J, Martin KA. Ten-Eleven Translocation-2 (TET2) Is a Master Regulator of Smooth Muscle Cell Plasticity. Circulation 2013, 128: 2047-2057. PMID: 24077167, PMCID: PMC3899790, DOI: 10.1161/circulationaha.113.002887.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAtherosclerosisCell DifferentiationCells, CulturedDioxygenasesDNA-Binding ProteinsEpigenesis, GeneticHumansKruppel-Like Factor 4Kruppel-Like Transcription FactorsMiceMice, KnockoutMuscle, Smooth, VascularMyocytes, Smooth MuscleNuclear ProteinsPromoter Regions, GeneticProto-Oncogene ProteinsTrans-ActivatorsWound HealingConceptsTen-Eleven Translocation-2SMC differentiationTET2 knockdownSmooth muscle cellsGene expressionTranslocation 2Smooth Muscle Cell PlasticityMaster epigenetic regulatorSMC gene expressionContractile gene expressionMuscle cell plasticityDedifferentiated smooth muscle cellsTET2 overexpressionContractile smooth muscle cellsHuman smooth muscle cellsChromatin accessibilityEpigenetic landscapeSMC plasticityChromatin immunoprecipitationEpigenetic regulatorsEpigenetic mechanismsCell plasticityMaster regulatorSMC phenotypeTranscriptional upregulation
2011
Prostacyclin receptor regulation--from transcription to trafficking.
Midgett C, Stitham J, Martin K, Hwa J. Prostacyclin receptor regulation--from transcription to trafficking. 2011, 11: 517-28. PMID: 21707517, PMCID: PMC3647249, DOI: 10.2174/156652411800615144.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsMouse knockout studiesReceptor regulationTransmembrane G-proteinKnockout studiesG proteinsCell surfaceRegulatory processesNon-selective COX-1/COXCorrect functionTranscriptionHigh cardiovascular risk patientsImportant receptorProstacyclin receptorImportant cardioprotective rolePrevention of atherothrombosisCardiovascular risk patientsIncreased cardiovascular eventsCOX-1/COXRegulationReceptorsCardiovascular eventsRisk patientsReceptor dysfunctionCardioprotective roleIP receptor
2010
Activation of Hedgehog Signaling by the Environmental Toxicant Arsenic May Contribute to the Etiology of Arsenic-Induced Tumors
Fei D, Li H, Kozul C, Black K, Singh S, Gosse J, DiRenzo J, Martin K, Wang B, Hamilton J, Karagas M, Robbins D. Activation of Hedgehog Signaling by the Environmental Toxicant Arsenic May Contribute to the Etiology of Arsenic-Induced Tumors. Cancer Research 2010, 70: 1981-1988. PMID: 20179202, PMCID: PMC2831120, DOI: 10.1158/0008-5472.can-09-2898.Peer-Reviewed Original ResearchConceptsArsenic exposureBladder cancerEnvironmental toxicant arsenicBladder cancer patientsSignificant health problemVariety of tumorsHedgehog signalingCancer patientsHealth problemsHigh levelsTumor samplesCancerHedgehog activitySame cancerHuman carcinogenesisMillions of peopleEtiologyTumorsExposureProgressionHedgehogTissue culture cellsActivationSignalingPatients
2008
Prostacyclin primes pregnant human myometrium for an enhanced contractile response in parturition
Fetalvero KM, Zhang P, Shyu M, Young BT, Hwa J, Young RC, Martin KA. Prostacyclin primes pregnant human myometrium for an enhanced contractile response in parturition. Journal Of Clinical Investigation 2008, 118: 3966-3979. PMID: 19033666, PMCID: PMC2582928, DOI: 10.1172/jci33800.Peer-Reviewed Original ResearchConceptsEnhanced contractile responseContractile responseMyometrial activationConnexin 43Contractile proteinsStrong phasic contractionsMaximal contractile responseHuman myometrial tissueOnset of laborPGI2 analog iloprostSmooth muscle relaxantPregnant human myometriumGap junction protein connexin 43Preterm laborPhasic contractionsPregnant stateProtein connexin 43Contractile agonistsMuscle relaxantsAnalogue iloprostHuman myometriumPGI2 receptorCOX-2Smooth muscleMyometrial tissue
2007
Regulation of vascular smooth muscle cell differentiation
Rzucidlo E, Martin K, Powell R. Regulation of vascular smooth muscle cell differentiation. Journal Of Vascular Surgery 2007, 45: a25-a32. PMID: 17544021, DOI: 10.1016/j.jvs.2007.03.001.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsVascular smooth muscle cell differentiationSmooth muscle cell differentiationMuscle cell differentiationCell differentiationPathogenesis of atherosclerosisMajor human diseasesLocal environmental cuesEnvironmental cuesContractile roleIntimal hyperplasiaDifferentiated stateVascular aneurysmsMolecular mechanismsVascular developmentPhenotypic switchingHuman diseasesVessel wallVSMCCritical roleDifferentiationEssential componentHypertensionAsthmaAtherosclerosisHyperplasia
2006
Rapamycin inhibits cell motility by suppression of mTOR-mediated S6K1 and 4E-BP1 pathways
Liu L, Li F, Cardelli J, Martin K, Blenis J, Huang S. Rapamycin inhibits cell motility by suppression of mTOR-mediated S6K1 and 4E-BP1 pathways. Oncogene 2006, 25: 7029-7040. PMID: 16715128, DOI: 10.1038/sj.onc.1209691.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAnimalsCattleCell Cycle ProteinsCell LineCell MovementCytoprotectionDown-RegulationEnzyme ActivationHumansInsulin-Like Growth Factor IMicePhosphoproteinsPhosphorylationProtein KinasesRibosomal Protein S6 Kinases, 70-kDaSerumSignal TransductionSirolimusTOR Serine-Threonine KinasesTranscription FactorsConceptsCell motilityRNA interferenceEukaryotic initiation factor 4EDownregulation of RaptorType I insulin-like growth factorMTOR kinase activityInitiation factor 4ES6 kinase 1Rapamycin inhibitionTumor cell motilityResistant mutantsSuppression of mTORP70 S6K1Kinase activityKinase 1S6K1Mammalian targetRapamycinProtein 1Effect of rapamycinConsequence of inhibitionCell linesMutantsRaptorsMotility
2002
The Critical Role of Transmembrane Prolines in Human Prostacyclin Receptor Activation
Stitham J, Martin KA, Hwa J. The Critical Role of Transmembrane Prolines in Human Prostacyclin Receptor Activation. Molecular Pharmacology 2002, 61: 1202-1210. PMID: 11961139, DOI: 10.1124/mol.61.5.1202.Peer-Reviewed Original ResearchConceptsG protein-coupled receptorsHuman prostacyclin receptorTransmembrane prolinesMolecular hingeProtein-coupled receptorsVascular smooth muscle relaxationProstacyclin receptor activationAlanine mutationsExtracellular boundarySmooth muscle relaxationPro-89Proline residuesLigand bindingGPCR activationExtracellular locationProper bindingWild-type controlsPosition 89ProlineMuscle relaxationPlatelet aggregationReceptor activationProstacyclin receptorCritical roleBinding
2000
Ribosomal S6 Kinase 2 Inhibition by a Potent C-terminal Repressor Domain Is Relieved by Mitogen-activated Protein-Extracellular Signal-regulated Kinase Kinase-regulated Phosphorylation*
Martin K, Schalm S, Romanelli A, Keon K, Blenis J. Ribosomal S6 Kinase 2 Inhibition by a Potent C-terminal Repressor Domain Is Relieved by Mitogen-activated Protein-Extracellular Signal-regulated Kinase Kinase-regulated Phosphorylation*. Journal Of Biological Chemistry 2000, 276: 7892-7898. PMID: 11108720, DOI: 10.1074/jbc.m009972200.Peer-Reviewed Original ResearchMeSH KeywordsButadienesCells, CulturedEnzyme ActivationEpidermal Growth FactorHumansIsoenzymesMitogen-Activated Protein Kinase 1Mitogen-Activated Protein Kinase 3Mitogen-Activated Protein Kinase KinasesMitogen-Activated Protein KinasesNitrilesPhosphatidylinositol 3-KinasesPhosphorylationRibosomal Protein S6 KinasesConceptsNuclear localization signalLocalization signalPhosphorylation sitesProtein kinaseMitogen-activated protein kinase phosphorylation siteC-terminal nuclear localization signalSerine/threonine protein kinaseProtein kinase phosphorylation siteSignal-regulated kinase kinaseRibosomal S6 kinase 2C-terminal phosphorylation sitesC-terminal repressor domainThreonine protein kinaseKinase phosphorylation siteC-terminal motifMitogen-activated protein kinasePhosphorylation site mutationsS6 kinase 2C-terminal domainKinase kinase inhibitor U0126Ribosomal protein S6C-terminal deletionsC-terminal regionKinase inhibitor U0126Site-specific mutations