Featured Publications
Platelet-derived TLT-1 promotes tumor progression by suppressing CD8+ T cells
Tyagi T, Jain K, Yarovinsky TO, Chiorazzi M, Du J, Castro C, Griffin J, Korde A, Martin KA, Takyar SS, Flavell RA, Patel AA, Hwa J. Platelet-derived TLT-1 promotes tumor progression by suppressing CD8+ T cells. Journal Of Experimental Medicine 2022, 220: e20212218. PMID: 36305874, PMCID: PMC9814191, DOI: 10.1084/jem.20212218.Peer-Reviewed Original ResearchConceptsCD8 T cellsT cellsTLT-1Non-small cell lung cancer patientsCell lung cancer patientsTREM-like transcript-1Tumor immunosuppressive mechanismsT cell suppressionLung cancer patientsPatient T cellsNF-κB pathwayPatient-derived tumorsDistinct activation phenotypesNSCLC patientsImmunosuppressive mechanismsSyngeneic tumorsHumanized miceImmunoregulatory rolePrognostic significanceImmunocompetent miceCancer patientsCell suppressionActivation phenotypeReduced tumorTumor growthUnfolded Protein Response Differentially Modulates the Platelet Phenotype
Jain K, Tyagi T, Du J, Hu X, Patell K, Martin KA, Hwa J. Unfolded Protein Response Differentially Modulates the Platelet Phenotype. Circulation Research 2022, 131: 290-307. PMID: 35862006, PMCID: PMC9357223, DOI: 10.1161/circresaha.121.320530.Peer-Reviewed Original ResearchConceptsUPR pathwayProtein responseMouse plateletsUnfolded protein responseActivation of UPRPlatelet phenotypeTranscriptional regulationGenomic regulationProtein misfoldingAnucleate plateletsProtein aggregationUPR activationPhosphorylation of PLCγ2Chemical chaperonesXBP1 pathwayP38 MAPKPERK pathwayUPRPKCδ activationPlatelet physiologyActivation pathwayPathwayPhenotypeIRE1α inhibitionSelective inductionSOD2 in platelets: with age comes responsibility
Jain K, Gu S, Hwa J. SOD2 in platelets: with age comes responsibility. Journal Of Thrombosis And Haemostasis 2023, 21: 1077-1081. PMID: 36716965, DOI: 10.1016/j.jtha.2023.01.016.Peer-Reviewed Original Research
2023
The 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
2022
Histone Acetyltransferases p300 and CBP Coordinate Distinct Chromatin Remodeling Programs in Vascular Smooth Muscle Plasticity
Chakraborty R, Ostriker AC, Xie Y, Dave JM, Gamez-Mendez A, Chatterjee P, Abu Y, Valentine J, Lezon-Geyda K, Greif DM, Schulz VP, Gallagher PG, Sessa WC, Hwa J, Martin KA. Histone Acetyltransferases p300 and CBP Coordinate Distinct Chromatin Remodeling Programs in Vascular Smooth Muscle Plasticity. Circulation 2022, 145: 1720-1737. PMID: 35502657, DOI: 10.1161/circulationaha.121.057599.Peer-Reviewed Original ResearchConceptsHistone acetylationContractile genesContractile protein expressionPhenotypic switchingHistone acetyl transferase p300Human intimal hyperplasiaPlatelet-derived growth factor treatmentAcetyl transferase p300Key regulatory mechanismSmooth muscle cell phenotypeP300 expressionP300-dependent acetylationSmooth muscle plasticityDistinct functional interactionsMuscle cell phenotypeProtein expressionIntimal hyperplasiaRole of p300Methylcytosine dioxygenase TET2Chromatin modificationsEpigenetic regulationVSMC phenotypic switchingSpecific histoneCardiovascular diseaseMaster regulatorGasdermin D inhibition confers antineutrophil mediated cardioprotection in acute myocardial infarction
Jiang K, Tu Z, Chen K, Xu Y, Chen F, Xu S, Shi T, Qian J, Shen L, Hwa J, Wang D, Xiang Y. Gasdermin D inhibition confers antineutrophil mediated cardioprotection in acute myocardial infarction. Journal Of Clinical Investigation 2022, 132: e151268. PMID: 34752417, PMCID: PMC8718151, DOI: 10.1172/jci151268.Peer-Reviewed Original ResearchConceptsAcute myocardial infarctionGasdermin DInfarcted heartMyocardial infarctionBone marrow transplantation studiesAMI mouse modelIL-1β releaseMarrow transplantation studiesReduced heart failureBlood leukocytosisDetrimental immunopathologyEarly mobilizationHeart failureInfarct sizePatient survivalVentricular remodelingCardiac functionAMI survivalMouse modelHeart functionExcessive boneNeutrophil productionNeutrophil generationScar sizePharmacological inhibition
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
Circular 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
Age associated non-linear regulation of redox homeostasis in the anucleate platelet: Implications for CVD risk patients
Jain K, Tyagi T, Patell K, Xie Y, Kadado AJ, Lee SH, Yarovinsky T, Du J, Hwang J, Martin KA, Testani J, Ionescu CN, Hwa J. Age associated non-linear regulation of redox homeostasis in the anucleate platelet: Implications for CVD risk patients. EBioMedicine 2019, 44: 28-40. PMID: 31130473, PMCID: PMC6604369, DOI: 10.1016/j.ebiom.2019.05.022.Peer-Reviewed Original ResearchMeSH KeywordsAdaptation, PhysiologicalAge FactorsAgedAged, 80 and overAgingAnimalsAntioxidantsApoptosisBiomarkersBlood PlateletsCardiovascular DiseasesComorbidityDisease Models, AnimalFemaleHomeostasisHumansMaleMiceMiddle AgedOxidation-ReductionOxidative StressPlatelet ActivationPlatelet AdhesivenessReactive Oxygen SpeciesRisk AssessmentRisk FactorsConceptsRisk patientsMouse studiesPlatelet phenotypeMajor adverse cardiovascular eventsHigh cardiovascular risk patientsAdaptive increaseAdverse cardiovascular eventsCentral pathophysiological roleCVD risk patientsCardiovascular risk patientsAggressive antiplatelet therapyEffect of comorbidityAge group 40Young healthy subjectsAntiplatelet therapyCardiovascular eventsYear age cohortAdvanced ageCVD patientsGroup 40Healthy subjectsPathophysiological roleElderly populationCardiovascular pathologyPatientsPlatelet-derived miR-223 promotes a phenotypic switch in arterial injury repair
Zeng Z, Xia L, Fan X, Ostriker AC, Yarovinsky T, Su M, Zhang Y, Peng X, Xie Y, Pi L, Gu X, Chung SK, Martin KA, Liu R, Hwa J, Tang WH. Platelet-derived miR-223 promotes a phenotypic switch in arterial injury repair. Journal Of Clinical Investigation 2019, 129: 1372-1386. PMID: 30645204, PMCID: PMC6391113, DOI: 10.1172/jci124508.Peer-Reviewed Original ResearchConceptsArterial injuryInjury repairMiR-223Intimal hyperplasiaVSMC dedifferentiationArterial injury repairArterial wire injuryPlatelet-derived miRNAsVascular injury repairVSMC phenotypic switchingInjury-induced dedifferentiationMiR-223 mimicsDiabetic miceEndothelial denudationWire injuryReporter miceUptake of GFPInjuryHyperplasiaVSMCsReduced expressionVivo studiesPhenotypic switchMiceSignificant increase
2016
The Wnt Antagonist Dickkopf-1 Promotes Pathological Type 2 Cell-Mediated Inflammation
Chae WJ, Ehrlich AK, Chan PY, Teixeira AM, Henegariu O, Hao L, Shin JH, Park JH, Tang WH, Kim ST, Maher SE, Goldsmith-Pestana K, Shan P, Hwa J, Lee PJ, Krause DS, Rothlin CV, McMahon-Pratt D, Bothwell AL. The Wnt Antagonist Dickkopf-1 Promotes Pathological Type 2 Cell-Mediated Inflammation. Immunity 2016, 44: 246-258. PMID: 26872695, PMCID: PMC4758884, DOI: 10.1016/j.immuni.2016.01.008.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntigens, DermatophagoidesAntigens, ProtozoanAsthmaBlood PlateletsCell DifferentiationCells, CulturedCytokinesExtracellular Signal-Regulated MAP KinasesGene Expression RegulationHumansInflammationIntercellular Signaling Peptides and ProteinsLeishmania majorLeishmaniasis, CutaneousMiceMice, Inbred BALB CMice, Inbred C57BLMice, TransgenicModels, AnimalPyroglyphidaeSignal TransductionTh2 CellsTOR Serine-Threonine KinasesWnt ProteinsConceptsCell-mediated inflammationTh2 cell cytokine productionCell cytokine productionLeukocyte-platelet aggregatesLeukocyte infiltrationDkk-1Cytokine productionT helper 2 cellsLeishmania major infectionHouse dust miteTranscription factor c-MafAllergen challengeMajor infectionDust miteImmune responseDickkopf-1Parasitic infectionsGATA-3Pathological roleFunctional inhibitionInflammationC-MafP38 MAPKInfiltrationInfection
2015
Hyperglycemia repression of miR-24 coordinately upregulates endothelial cell expression and secretion of von Willebrand factor
Xiang Y, Cheng J, Wang D, Hu X, Xie Y, Stitham J, Atteya G, Du J, Tang WH, Lee SH, Leslie K, Spollett G, Liu Z, Herzog E, Herzog RI, Lu J, Martin KA, Hwa J. Hyperglycemia repression of miR-24 coordinately upregulates endothelial cell expression and secretion of von Willebrand factor. Blood 2015, 125: 3377-3387. PMID: 25814526, PMCID: PMC4447857, DOI: 10.1182/blood-2015-01-620278.Peer-Reviewed Original ResearchConceptsVon Willebrand factorDiabetes mellitusMiR-24Diabetic patientsAdverse thrombotic eventsThrombotic cardiovascular eventsVWF expressionWillebrand factorDiabetic mouse modelNovel therapeutic targetHistamine H1 receptorsEndothelial cell expressionHyperglycemia-induced activationCardiovascular eventsThrombotic eventsH1 receptorsMouse modelVWF levelsTherapeutic targetCell expressionMellitusPatientsEndothelial cellsElevated levelsReactive oxygen species
2014
Aldose Reductase–Mediated Phosphorylation of p53 Leads to Mitochondrial Dysfunction and Damage in Diabetic Platelets
Tang WH, Stitham J, Jin Y, Liu R, Lee SH, Du J, Atteya G, Gleim S, Spollett G, Martin K, Hwa J. Aldose Reductase–Mediated Phosphorylation of p53 Leads to Mitochondrial Dysfunction and Damage in Diabetic Platelets. Circulation 2014, 129: 1598-1609. PMID: 24474649, PMCID: PMC3989377, DOI: 10.1161/circulationaha.113.005224.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAldehyde ReductaseAnimalsApoptosisBcl-X ProteinBlood PlateletsCarotid Artery DiseasesDiabetes Mellitus, ExperimentalDiabetes Mellitus, Type 2Disease Models, AnimalFemaleHumansMaleMiceMice, Inbred C57BLMice, KnockoutMiddle AgedMitochondrial DiseasesPhosphorylationSignal TransductionThrombosisTumor Suppressor Protein p53ConceptsMitochondrial dysfunctionHyperglycemia-induced mitochondrial dysfunctionP53 phosphorylationAntiapoptotic protein Bcl-xL.Platelet apoptosisMitochondrial damageMitochondrial membrane potentialReductase activationActivation of p53Reactive oxygen species productionOxygen species productionBcl-xL.Molecular pathwaysSevere mitochondrial damagePhosphorylationNovel therapeutic targetAldose reductase activationSpecies productionMembrane potentialApoptosisCentral roleTherapeutic targetDose-dependent mannerActivationP53
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