2022
Gasdermin 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
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 dataEndotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study
Goshua G, Pine AB, Meizlish ML, Chang CH, Zhang H, Bahel P, Baluha A, Bar N, Bona RD, Burns AJ, Dela Cruz CS, Dumont A, Halene S, Hwa J, Koff J, Menninger H, Neparidze N, Price C, Siner JM, Tormey C, Rinder HM, Chun HJ, Lee AI. Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study. The Lancet Haematology 2020, 7: e575-e582. PMID: 32619411, PMCID: PMC7326446, DOI: 10.1016/s2352-3026(20)30216-7.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overBetacoronavirusBiomarkersBlood Coagulation DisordersCoronavirus InfectionsCOVID-19Critical IllnessCross-Sectional StudiesEndothelium, VascularFemaleFollow-Up StudiesHumansIntensive Care UnitsMaleMiddle AgedPandemicsPneumonia, ViralPrognosisSARS-CoV-2Vascular DiseasesYoung AdultConceptsCOVID-19-associated coagulopathyNon-ICU patientsIntensive care unitKaplan-Meier analysisSoluble P-selectinCross-sectional studyPlatelet activationHospital dischargeICU patientsSoluble thrombomodulinEndothelial cellsVWF antigenCOVID-19P-selectinSingle-center cross-sectional studyLaboratory-confirmed COVID-19Medical intensive care unitSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogenesisVon Willebrand factor antigenSoluble thrombomodulin concentrationsVWF antigen concentrationEndothelial cell injurySoluble CD40 ligandMicrovascular complicationsAdult patientsReduced Platelet miR-223 Induction in Kawasaki Disease Leads to Severe Coronary Artery Pathology Through a miR-223/PDGFRβ Vascular Smooth Muscle Cell Axis
Zhang Y, Wang Y, Zhang L, Xia L, Zheng M, Zeng Z, Liu Y, Yarovinsky T, Ostriker AC, Fan X, Weng K, Su M, Huang P, Martin KA, Hwa J, Tang WH. Reduced Platelet miR-223 Induction in Kawasaki Disease Leads to Severe Coronary Artery Pathology Through a miR-223/PDGFRβ Vascular Smooth Muscle Cell Axis. Circulation Research 2020, 127: 855-873. PMID: 32597702, PMCID: PMC7486265, DOI: 10.1161/circresaha.120.316951.Peer-Reviewed Original ResearchMeSH KeywordsAdultAge FactorsAnimalsBlood PlateletsCase-Control StudiesCells, CulturedChildChild, PreschoolCoronary Artery DiseaseCoronary VesselsDisease Models, AnimalFemaleHumansInfantMaleMice, Inbred C57BLMice, KnockoutMicroRNAsMucocutaneous Lymph Node SyndromeMuscle, Smooth, VascularMyocytes, Smooth MusclePlatelet ActivationProspective StudiesReceptor, Platelet-Derived Growth Factor betaSeverity of Illness IndexSignal TransductionYoung AdultConceptsSevere coronary pathologyCoronary artery pathologyKawasaki diseaseCoronary pathologyArtery pathologyMiR-223Medial damageHealthy controlsVSMC dedifferentiationHallmark of KDMiR-223 knockout miceVascular smooth muscle cell dedifferentiationSmooth muscle cell dedifferentiationPlatelet miR-223Platelet-derived miRNAsVSMC differentiationMedial elastic fibersMiR-223 levelsMuscle cell dedifferentiationPotential therapeutic strategyInhibitor imatinib mesylateVascular smooth muscle cell phenotypeSmooth muscle cell phenotypeMiR-223 mimicsUptake of platelets
2019
CELA2A mutations predispose to early-onset atherosclerosis and metabolic syndrome and affect plasma insulin and platelet activation
Esteghamat F, Broughton JS, Smith E, Cardone R, Tyagi T, Guerra M, Szabó A, Ugwu N, Mani MV, Azari B, Kayingo G, Chung S, Fathzadeh M, Weiss E, Bender J, Mane S, Lifton RP, Adeniran A, Nathanson MH, Gorelick FS, Hwa J, Sahin-Tóth M, Belfort-DeAguiar R, Kibbey RG, Mani A. CELA2A mutations predispose to early-onset atherosclerosis and metabolic syndrome and affect plasma insulin and platelet activation. Nature Genetics 2019, 51: 1233-1243. PMID: 31358993, PMCID: PMC6675645, DOI: 10.1038/s41588-019-0470-3.Peer-Reviewed Original ResearchConceptsEarly-onset atherosclerosisMetabolic syndromeMetabolic syndrome traitsWhole-exome sequence analysisAttractive therapeutic targetPlatelet hyperactivationInsulin levelsPlasma insulinPlasma levelsInsulin sensitivityInsulin secretionTherapeutic targetPlatelet activationDisease mechanismsSyndrome traitsAtherosclerosisFunction mutationsSyndromeNovel lossInsulinMutationsSecretionAge 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 increaseLMO7 Is a Negative Feedback Regulator of Transforming Growth Factor β Signaling and Fibrosis
Xie Y, Ostriker AC, Jin Y, Hu H, Sizer AJ, Peng G, Morris AH, Ryu C, Herzog EL, Kyriakides T, Zhao H, Dardik A, Yu J, Hwa J, Martin KA. LMO7 Is a Negative Feedback Regulator of Transforming Growth Factor β Signaling and Fibrosis. Circulation 2019, 139: 679-693. PMID: 30586711, PMCID: PMC6371979, DOI: 10.1161/circulationaha.118.034615.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell ProliferationCells, CulturedDisease Models, AnimalExtracellular MatrixFeedback, PhysiologicalFibrosisHyperplasiaIntegrin alphaVbeta3LIM Domain ProteinsMaleMice, Inbred C57BLMice, KnockoutMuscle, Smooth, VascularMyocytes, Smooth MuscleNeointimaSignal TransductionTranscription Factor AP-1Transcription FactorsTransforming Growth Factor beta1Vascular RemodelingVascular System InjuriesConceptsSmooth muscle cellsActivator protein-1 (AP-1) transcription factorExtracellular matrixProtein-1 transcription factorTransforming Growth Factor β SignalingGrowth factor β signalingMouse smooth muscle cellsTGF-β1 target genesHuman smooth muscle cellsActivator protein-1Muscle-specific deletionNegative feedback regulatorTGF-β pathwayECM protein expressionSmad3 phosphorylationNegative feedback regulationTranscription factorsArteriovenous fistulaECM depositionDomain interactsTGF-β proteinTarget genesLMO7TGF-β treatmentGrowth factor β
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
A Form of the Metabolic Syndrome Associated with Mutations in DYRK1B
Keramati AR, Fathzadeh M, Go GW, Singh R, Choi M, Faramarzi S, Mane S, Kasaei M, Sarajzadeh-Fard K, Hwa J, Kidd KK, Babaee Bigi MA, Malekzadeh R, Hosseinian A, Babaei M, Lifton RP, Mani A. A Form of the Metabolic Syndrome Associated with Mutations in DYRK1B. New England Journal Of Medicine 2014, 370: 1909-1919. PMID: 24827035, PMCID: PMC4069260, DOI: 10.1056/nejmoa1301824.Peer-Reviewed Original ResearchConceptsKinase-like domainMapping susceptibility genesHistidine 90Disease-causing genesFunctional characterizationDisease genesDYRK1BKey gluconeogenic enzymesGenetic analysisCardiovascular risk traitsWhole-exome sequencingDistinct familiesLinkage analysisSecond mutationPosition 102Susceptibility genesFamily membersLarge familyGenesCausative mutationsUnaffected family membersMutationsFunction activityAffected family membersGluconeogenic enzymesAldose 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
Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome
Lemaire M, Frémeaux-Bacchi V, Schaefer F, Choi M, Tang WH, Le Quintrec M, Fakhouri F, Taque S, Nobili F, Martinez F, Ji W, Overton JD, Mane SM, Nürnberg G, Altmüller J, Thiele H, Morin D, Deschenes G, Baudouin V, Llanas B, Collard L, Majid MA, Simkova E, Nürnberg P, Rioux-Leclerc N, Moeckel GW, Gubler MC, Hwa J, Loirat C, Lifton RP. Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome. Nature Genetics 2013, 45: 531-536. PMID: 23542698, PMCID: PMC3719402, DOI: 10.1038/ng.2590.Peer-Reviewed Original ResearchMeSH KeywordsAcute Kidney InjuryAtypical Hemolytic Uremic SyndromeChildChild, PreschoolDiacylglycerol KinaseExomeFemaleGenes, RecessiveHemolytic-Uremic SyndromeHumansImmunoenzyme TechniquesInfantMaleMolecular Sequence DataMutationRenal Insufficiency, ChronicThrombocytopeniaThrombotic Microangiopathies