Featured Publications
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 regulatorJAGGED1/NOTCH3 activation promotes aortic hypermuscularization and stenosis in elastin deficiency
Dave JM, Chakraborty R, Ntokou A, Saito J, Saddouk FZ, Feng Z, Misra A, Tellides G, Riemer RK, Urban Z, Kinnear C, Ellis J, Mital S, Mecham R, Martin KA, Greif DM. JAGGED1/NOTCH3 activation promotes aortic hypermuscularization and stenosis in elastin deficiency. Journal Of Clinical Investigation 2022, 132: e142338. PMID: 34990407, PMCID: PMC8884911, DOI: 10.1172/jci142338.Peer-Reviewed Original ResearchConceptsSmooth muscle cellsSupravalvular aortic stenosisEndothelial cellsElastin insufficiencyObstructive arterial diseaseAortic smooth muscle cellsΓ-secretaseAortic vascular cellsPotential therapeutic targetNotch3 intracellular domainNotch ligand Jagged1Aortic stenosisArterial diseasePathological featuresPharmacological treatmentJag1 deletionLuminal obstructionMouse modelNotch3 activationTherapeutic targetSMC accumulationPathway upregulationAortic samplesMice displayNotch3 deletionTET2 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 failureTargeting smooth muscle cell phenotypic switching in vascular disease
Chakraborty R, Chatterjee P, Dave JM, Ostriker AC, Greif DM, Rzucidlo EM, Martin KA. Targeting smooth muscle cell phenotypic switching in vascular disease. JVS Vascular Science 2021, 2: 79-94. PMID: 34617061, PMCID: PMC8489222, DOI: 10.1016/j.jvssci.2021.04.001.Peer-Reviewed Original ResearchSingle-cell transcriptomicsVascular smooth muscle cellsVSMC phenotypic modulationPhenotypic plasticityCell transcriptomicsPhenotypic modulationMature vascular smooth muscle cellsSmooth muscle cell phenotypicLineage tracing methodStriking diversityFundamental new insightsMolecular mechanismsFate mappingRemarkable plasticityBromodomain inhibitorsHistone deacetylasePhenotypic switchingPharmacologic inhibitorsGenetic targetingVSMC phenotypicDruggable pathwaysSmooth muscle cellsOligoclonal lesionsTranscriptomicsRecent discovery
2024
Endothelial γ-protocadherins inhibit KLF2 and KLF4 to promote atherosclerosis
Joshi D, Coon B, Chakraborty R, Deng H, Yang Z, Babar M, Fernandez-Tussy P, Meredith E, Attanasio J, Joshi N, Traylor J, Orr A, Fernandez-Hernando C, Libreros S, Schwartz M. Endothelial γ-protocadherins inhibit KLF2 and KLF4 to promote atherosclerosis. Nature Cardiovascular Research 2024, 3: 1035-1048. PMID: 39232138, PMCID: PMC11399086, DOI: 10.1038/s44161-024-00522-z.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAtherosclerosisCadherin Related ProteinsCadherinsDisease Models, AnimalEndothelial CellsHuman Umbilical Vein Endothelial CellsHumansKruppel-Like Factor 4Kruppel-Like Transcription FactorsMaleMiceMice, Inbred C57BLMice, KnockoutPlaque, AtheroscleroticReceptors, NotchSignal TransductionConceptsAtherosclerotic cardiovascular diseaseIntracellular domainNotch intracellular domainTranscription factor KLF2Mechanisms of vascular inflammationAnti-inflammatory programVascular endothelial cellsHost defenseCleavage resultsAntibody blockadeGenetic deletionVascular inflammationViral infectionImmune systemEndothelial cellsCardiovascular diseasePromote atherosclerosisBlood flowKLF2KLF4Suppressive signalsEndotheliumMechanistic studiesLoss of TGFβ-Mediated Repression of Angiopoietin-2 in Pericytes Underlies Germinal Matrix Hemorrhage Pathogenesis
Dave J, Chakraborty R, Agyemang A, Ntokou A, Saito J, Ballabh P, Martin K, Greif D. Loss of TGFβ-Mediated Repression of Angiopoietin-2 in Pericytes Underlies Germinal Matrix Hemorrhage Pathogenesis. Stroke 2024, 55: 2340-2352. PMID: 39129597, PMCID: PMC11347087, DOI: 10.1161/strokeaha.123.045248.Peer-Reviewed Original ResearchAngiopoietin-2Germinal matrix hemorrhage-intraventricular hemorrhagePerinatal lethalityEndothelial cell hyperproliferationEndothelial cellsBrain pericytesGenetic inhibitionVascular cellsBlood-brain barrier integrityBlood-brain barrier developmentBrain vascular cellsAbnormal vessel morphologyVessel morphologyProlonged survivalRegulating cross-talkMutant endothelial cellsHuman brain pericytesGerminal matrixCell hyperproliferationPhosphorylates Tie2Embryonic miceCellular sourceBarrier integrityGenetic ablationTherapeutic effectAbstract 2121: SUV39H1 Mediated Regulation Of KLF4 And KDM4a Coordinate Smooth Muscle Cell Phenotypic Plasticity
Chatterjee P, Chakraborty R, Sizer A, Xie Y, Hwa J, Martin K. Abstract 2121: SUV39H1 Mediated Regulation Of KLF4 And KDM4a Coordinate Smooth Muscle Cell Phenotypic Plasticity. Arteriosclerosis Thrombosis And Vascular Biology 2024, 44 DOI: 10.1161/atvb.44.suppl_1.2121.Peer-Reviewed Original ResearchRNA-seqPhenotypic plasticityEpigenetic regulationH3K9me3 repressive marksRNA-seq transcriptomicsContractile genesEpigenetic transcriptional repressionCell phenotypic plasticityH3K9me3 markExpression of SUV39H1Repressive marksTranscriptional repressionChromatin immunoprecipitationHistone methyltransferaseDedifferentiation in vitroIn vivoSUV39H1 knockdownH3K9me3MRNA stabilitySUV39H1Gene expressionPlasticity of vascular smooth muscle cellsRegulation of Klf4GenesH3K9me3 expressionAbstract 1147: Crosstalk Between Alk5 And Mtorc1 Signaling Promotes VSMC Differentiation And The Therapeutic Effect Of Rapamycin
Chakraborty R, Chatterjee P, Dave J, Obrien B, Joshi D, Schulz V, Greif D, Hwa J, Gallagher P, Martin K. Abstract 1147: Crosstalk Between Alk5 And Mtorc1 Signaling Promotes VSMC Differentiation And The Therapeutic Effect Of Rapamycin. Arteriosclerosis Thrombosis And Vascular Biology 2024, 44 DOI: 10.1161/atvb.44.suppl_1.1147.Peer-Reviewed Original ResearchVascular smooth muscle cellsTherapeutic effect of rapamycinEffects of rapamycinVSMC differentiationContractile genesConsistent with in vitro findingsRapamycin treatmentCarotid artery injuryHuman coronary artery SMCsVascular smooth muscle cell differentiationIntimal hyperplasiaSmooth muscle cellsCoronary artery SMCsMTORC1 inhibitor rapamycinPhosphorylation of Smad2/3Inhibition of ALK5Smad-binding elementSmad transcription factorsALK5 activityArterial injuryArtery SMCsKnockout miceInhibition of mTORC1Vascular smooth muscle cell plasticityMuscle cells
2023
Multimodality Platelet Evaluation By Mass Cytometry and Genetic Analysis in Patients with Bleeding Disorders
Gu S, Gallagher P, Butt A, Gu V, Lezon-Geyda K, Schulz V, Prozora S, Lee A, Neparidze N, Bar N, Martin K, Cornell J, Chirico G, Chakraborty R, Rinder H, Hwa J, Bona R. Multimodality Platelet Evaluation By Mass Cytometry and Genetic Analysis in Patients with Bleeding Disorders. Blood 2023, 142: 1197. DOI: 10.1182/blood-2023-177946.Peer-Reviewed Original ResearchBleeding tendencyBleeding disorderPlatelet markersPlatelet aggregometryMass cytometryPlatelet functionPlatelet disordersSingle-center prospective studyLow-risk groupAbnormal bleeding tendencyQualitative platelet disordersLarge patient cohortQuantitative platelet disordersCommon underlying causeGenetic variantsMultimodality evaluationTotal patientsRisk stratificationLaboratory suspicionPlatelet dysfunctionProspective studyPatient cohortUnivariate analysisPlatelet volumeRisk groupsThe 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
Low-dose Aspirin prevents hypertension and cardiac fibrosis when thromboxane A2 is unrestrained
D'Agostino I, Tacconelli S, Bruno A, Contursi A, Mucci L, Hu X, Xie Y, Chakraborty R, Jain K, Sacco A, Zucchelli M, Landolfi R, Dovizio M, Falcone L, Ballerini P, Hwa J, Patrignani P. Low-dose Aspirin prevents hypertension and cardiac fibrosis when thromboxane A2 is unrestrained. Pharmacological Research 2021, 170: 105744. PMID: 34182131, DOI: 10.1016/j.phrs.2021.105744.Peer-Reviewed Original ResearchMeSH KeywordsAdultAnimalsAntifibrotic AgentsAntihypertensive AgentsAspirinBiomarkersBlood PlateletsBlood PressureCardiomyopathiesCase-Control StudiesCells, CulturedDisease Models, AnimalEssential HypertensionFemaleFibrosisHumansMaleMice, Inbred C57BLMice, KnockoutMiddle AgedMyocytes, CardiacMyofibroblastsPlatelet Aggregation InhibitorsReceptors, EpoprostenolReceptors, ThromboxaneThromboxane A2ConceptsProfibrotic gene expressionEnhanced blood pressureBlood pressureCardiac fibrosisPlatelet TXAHypertensive patientsOverload-induced cardiac fibrosisLow-dose aspirin administrationEarly cardiac fibrosisPlatelet-derived thromboxaneLow-dose aspirinEssential hypertensive patientsEssential hypertension patientsHigh-salt dietSalt-sensitive hypertensionCardiac collagen depositionNumber of myofibroblastsSelective inhibitionGene expressionPrevents hypertensionTP overexpressionUrinary TXMAspirin administrationHypertensive miceAspirin treatment
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
Chapter 8 Characterization of GPCR signaling in hypoxia
Chakraborty R, Sikarwar A, Hinton M, Dakshinamurti S, Chelikani P. Chapter 8 Characterization of GPCR signaling in hypoxia. Methods In Cell Biology 2017, 142: 101-110. PMID: 28964329, DOI: 10.1016/bs.mcb.2017.07.005.Peer-Reviewed Original ResearchConceptsThromboxane A2 receptorG protein-coupled receptorsPrimary pulmonary artery smooth muscle cellsPulmonary artery smooth muscle cellsArtery smooth muscle cellsPersistent pulmonary hypertensionPulmonary arterial responsesKey G‐protein‐coupled receptorsSmooth muscle cellsPulmonary hypertensionProtein-coupled receptorsArterial responseTissue hypoxiaCardiovascular diseaseA2 receptorsT cellsProstanoid receptorsCell responsesMuscle cellsHypoxic experimentsGPCR signalingHypoxiaHEK293T cellsReceptorsOxygen supplyClonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice
Fuster JJ, MacLauchlan S, Zuriaga MA, Polackal MN, Ostriker AC, Chakraborty R, Wu CL, Sano S, Muralidharan S, Rius C, Vuong J, Jacob S, Muralidhar V, Robertson AA, Cooper MA, Andrés V, Hirschi KK, Martin KA, Walsh K. Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science 2017, 355: 842-847. PMID: 28104796, PMCID: PMC5542057, DOI: 10.1126/science.aag1381.Peer-Reviewed Original ResearchConceptsTET2-deficient cellsLow-density lipoprotein receptor-deficient miceLipoprotein receptor-deficient miceClonal hematopoiesisBlood cellsAtherosclerotic cardiovascular diseaseAtherosclerotic plaque sizeReceptor-deficient miceBone marrow reconstitutionInterleukin-1β secretionMutant blood cellsAtherosclerosis developmentNLRP3 inhibitorAtheroprotective activityCardiovascular diseaseMarrow reconstitutionChimeric micePlaque sizeClonal expansionMiceMarked increaseCausal roleTET2 deficiencySomatic mutationsHematopoietic cells
2016
The Pharmacochaperone Activity of Quinine on Bitter Taste Receptors
Upadhyaya J, Chakraborty R, Shaik F, Jaggupilli A, Bhullar R, Chelikani P. The Pharmacochaperone Activity of Quinine on Bitter Taste Receptors. PLOS ONE 2016, 11: e0156347. PMID: 27223611, PMCID: PMC4880206, DOI: 10.1371/journal.pone.0156347.Peer-Reviewed Original ResearchConceptsBitter taste receptorsBitter taste signal transductionTaste receptorsTaste signal transductionControl untreated cellsQuinine treatmentAgonist treatmentCell surface expressionCalcium responsePharmacological techniquesAgonist activityTaste sensationBitter agonistsBasic taste sensationsReceptor internalizationSurface expressionUntreated cellsQuinineTreatmentDesensitizationReceptorsSignal transductionObserved actions
2015
Chapter Twelve Expression of G Protein-Coupled Receptors in Mammalian Cells
Chakraborty R, Xu B, Bhullar R, Chelikani P. Chapter Twelve Expression of G Protein-Coupled Receptors in Mammalian Cells. Methods In Enzymology 2015, 556: 267-281. PMID: 25857786, DOI: 10.1016/bs.mie.2014.12.013.Peer-Reviewed Original Research
2014
Dextromethorphan Mediated Bitter Taste Receptor Activation in the Pulmonary Circuit Causes Vasoconstriction
Upadhyaya J, Singh N, Sikarwar A, Chakraborty R, Pydi S, Bhullar R, Dakshinamurti S, Chelikani P. Dextromethorphan Mediated Bitter Taste Receptor Activation in the Pulmonary Circuit Causes Vasoconstriction. PLOS ONE 2014, 9: e110373. PMID: 25340739, PMCID: PMC4207743, DOI: 10.1371/journal.pone.0110373.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsDextromethorphanFluorescent Antibody TechniqueGene Expression RegulationGene Knockdown TechniquesHumansIn Vitro TechniquesInositol 1,4,5-TrisphosphateLungMyocytes, Smooth MuscleMyographyMyosin Light ChainsPhosphorylationPulmonary ArteryReceptors, G-Protein-CoupledReverse Transcriptase Polymerase Chain ReactionRNA, MessengerSuperoxidesSus scrofaTasteVasoconstrictionConceptsPulmonary artery smooth muscle cellsArtery smooth muscle cellsHuman pulmonary artery smooth muscle cellsSmooth muscle cellsAirway ringsMuscle cellsVascular tonePulmonary circuitCalcium responseHuman airway smooth muscle cellsAirway smooth muscle cellsExpression of T2RsPulmonary vascular toneBitter taste receptor activationTaste receptor activationEx vivo studyVasoconstrictor responsesBitter taste receptorsMyographic studiesMuscle relaxationReceptor activationDextromethorphanSpecific shRNART-PCRVivo studiesDifferential expression of bitter taste receptors in non-cancerous breast epithelial and breast cancer cells
Singh N, Chakraborty R, Bhullar R, Chelikani P. Differential expression of bitter taste receptors in non-cancerous breast epithelial and breast cancer cells. Biochemical And Biophysical Research Communications 2014, 446: 499-503. PMID: 24613843, DOI: 10.1016/j.bbrc.2014.02.140.Peer-Reviewed Original ResearchConceptsBreast cancer cellsCancer cellsBitter taste receptorsMammary epithelial cellsMetastatic breast cancer cell line MDA-MB-231Epithelial cellsBreast cancer cell line MDA-MB-231Intracellular calcium mobilizationCancer cell line MDA-MB-231Cell line MDA-MB-231Taste receptorsBitter melon extractNon-cancerous breastCell line MCF-7G protein-coupled receptorsMDA-MB-231Protein-coupled receptorsHuman bitter taste receptorsEstrogen receptorCalcium mobilizationTumor growthMelon extractFlow cytometryMCF-10A.ReceptorsInverse Agonism of SQ 29,548 and Ramatroban on Thromboxane A2 Receptor
Chakraborty R, Bhullar RP, Dakshinamurti S, Hwa J, Chelikani P. Inverse Agonism of SQ 29,548 and Ramatroban on Thromboxane A2 Receptor. PLOS ONE 2014, 9: e85937. PMID: 24465800, PMCID: PMC3900440, DOI: 10.1371/journal.pone.0085937.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SubstitutionBlood PlateletsBridged Bicyclo Compounds, HeterocyclicCalcium SignalingCarbazolesDrug Evaluation, PreclinicalFatty Acids, UnsaturatedHEK293 CellsHumansHydrazinesInositol 1,4,5-TrisphosphateMutagenesis, Site-DirectedReceptors, Thromboxane A2, Prostaglandin H2SulfonamidesConceptsThromboxane A2 receptorG protein-coupled receptorsA2 receptorsBasal activityPathophysiological conditionsImportant pathophysiological roleInverse agonist propertiesHuman platelet functionSuch constitutive activityTP dysfunctionConstitutive activityPlatelet hyperactivityProtein-coupled receptorsCardiovascular diseaseThromboxane A2Pathophysiological roleT cellsPlatelet functionImportant therapeutic applicationsAgonist propertiesRamatrobanPlatelet activationInverse agonistInverse agonismNeutral antagonists
2013
High-Level Expression, Purification and Characterization of a Constitutively Active Thromboxane A2 Receptor Polymorphic Variant
Xu B, Chakraborty R, Eilers M, Dakshinamurti S, O’Neil J, Smith S, Bhullar R, Chelikani P. High-Level Expression, Purification and Characterization of a Constitutively Active Thromboxane A2 Receptor Polymorphic Variant. PLOS ONE 2013, 8: e76481. PMID: 24086743, PMCID: PMC3781061, DOI: 10.1371/journal.pone.0076481.Peer-Reviewed Original ResearchConceptsG protein-coupled receptorsHigh-level expressionThromboxane A2 receptorSuccessful high-level expressionCell linesHigh-resolution crystal structuresProper expression systemMammalian cell linesResolution crystal structureProtein-coupled receptorsSingle-step affinity purificationStep affinity purificationCircular dichroism spectropolarimetryMembrane proteinsActive mutantAffinity purificationExpression systemBiophysical characterizationConstitutive signalingT geneSecondary structure changesT mutantGenetic variantsDiffusible ligandsHomogeneous glycosylation