2024
In silico and in vitro models reveal the molecular mechanisms of hypocontractility caused by TPM1 M8R
Creso J, Gokhan I, Rynkiewicz M, Lehman W, Moore J, Campbell S. In silico and in vitro models reveal the molecular mechanisms of hypocontractility caused by TPM1 M8R. Frontiers In Physiology 2024, 15: 1452509. PMID: 39282088, PMCID: PMC11392859, DOI: 10.3389/fphys.2024.1452509.Peer-Reviewed Original ResearchDilated cardiomyopathyManifestation of dilated cardiomyopathyTropomyosin-actin interactionsIntact cardiac muscleIsometric twitch forceCardiac muscle disordersSevere heart failureHuman engineered heart tissueGenotype-phenotype relationshipsDose-dependent mannerDuration of contractionIn silico predictionIn vitro modelDepressed contractilityMutant tissueCardiac sarcomereLinkage studiesHeart failureTropomyosin chainTwitch contractionsCardiac thin filamentsInherited disorderMuscle disordersMutation pathogenicityCardiac muscle
2023
Increased length-dependent activation of human engineered heart tissue after chronic α1A-adrenergic agonist treatment: testing a novel heart failure therapy
Rupert C, López J, Cortez-Toledo E, De la Cruz Cabrera O, Chesler N, Simpson P, Campbell S, Baker A. Increased length-dependent activation of human engineered heart tissue after chronic α1A-adrenergic agonist treatment: testing a novel heart failure therapy. AJP Heart And Circulatory Physiology 2023, 324: h293-h304. PMID: 36637971, PMCID: PMC9886349, DOI: 10.1152/ajpheart.00279.2022.Peer-Reviewed Original ResearchConceptsHuman heart failureHeart failureAR stimulationChronic stimulationLength-dependent activationVehicle treatmentHeart tissueAdrenergic receptorsHuman EHTsAnimal heart failure modelNovel heart failure therapiesHeart failure therapyHeart failure modelMultiple preclinical modelsFailure therapyAgonist treatmentSeparate control experimentsPreclinical modelsDrug washoutTherapeutic effectTranslational significanceHuman myocardiumBaseline testingRNA-seq analysisPig myocardium
2022
Humanized Dsp ACM Mouse Model Displays Stress-Induced Cardiac Electrical and Structural Phenotypes
Stevens TL, Manring HR, Wallace MJ, Argall A, Dew T, Papaioannou P, Antwi-Boasiako S, Xu X, Campbell SG, Akar FG, Borzok MA, Hund TJ, Mohler PJ, Koenig SN, El Refaey M. Humanized Dsp ACM Mouse Model Displays Stress-Induced Cardiac Electrical and Structural Phenotypes. Cells 2022, 11: 3049. PMID: 36231013, PMCID: PMC9562631, DOI: 10.3390/cells11193049.Peer-Reviewed Original ResearchConceptsArrhythmogenic cardiomyopathyMouse modelStructural phenotypesFibro-fatty infiltrationFirst mouse modelHeart failureChamber dilationVentricular arrhythmiasPressure overloadArrhythmic eventsCardiac performanceCardiac stressSudden deathCardiovascular stressInherited disorderG variantConnexin 43MiceDesmosomal genesReduced expressionExternal stressorsACM familyDisease developmentMurine equivalentIncomplete penetranceMuscle LIM Protein Force-Sensing Mediates Sarcomeric Biomechanical Signaling in Human Familial Hypertrophic Cardiomyopathy
Riaz M, Park J, Sewanan LR, Ren Y, Schwan J, Das SK, Pomianowski PT, Huang Y, Ellis MW, Luo J, Liu J, Song L, Chen IP, Qiu C, Yazawa M, Tellides G, Hwa J, Young LH, Yang L, Marboe CC, Jacoby DL, Campbell SG, Qyang Y. Muscle LIM Protein Force-Sensing Mediates Sarcomeric Biomechanical Signaling in Human Familial Hypertrophic Cardiomyopathy. Circulation 2022, 145: 1238-1253. PMID: 35384713, PMCID: PMC9109819, DOI: 10.1161/circulationaha.121.056265.Peer-Reviewed Original ResearchConceptsHypertrophic cardiomyopathySarcomeric mutationsFamilial hypertrophic cardiomyopathySudden cardiac deathCardiac myosin heavy chainMechanism-based treatmentsDevelopment of hypertrophyActivated T cellsCalcineurin-nuclear factorForce productionPhenotypic expressionPluripotent stem cell-derived cardiomyocytesStem cell-derived cardiomyocytesHeart failureCardiac deathVentricular hypertrophyCell-derived cardiomyocytesCardiac contractilityPharmacological interventionsT cellsCardiac diseaseCardiac hypertrophyPatient-specific induced pluripotent stem cellsPharmacological meansTwitch relaxationGSK-3β Localizes to the Cardiac Z-Disc to Maintain Length Dependent Activation
Stachowski-Doll MJ, Papadaki M, Martin TG, Ma W, Gong HM, Shao S, Shen S, Muntu NA, Kumar M, Perez E, Martin JL, Moravec CS, Sadayappan S, Campbell SG, Irving T, Kirk JA. GSK-3β Localizes to the Cardiac Z-Disc to Maintain Length Dependent Activation. Circulation Research 2022, 130: 871-886. PMID: 35168370, PMCID: PMC8930626, DOI: 10.1161/circresaha.121.319491.Peer-Reviewed Original ResearchConceptsZ-discGSK-3βZ-disc proteinsCardiac Z-diskLength-dependent activationKnockout miceKinase localizationPhosphorylation sitesNegative regulatorGenetic knockdownVivo roleDependent activationNeonatal rat ventricular cardiomyocytesNovel mechanismGSK-3β levelsHeart failureMyofilament localizationTitin phosphorylationVentricular myocardiumPossible therapeutic targetTitin isoformsTitin stiffnessTherapeutic targetPassive tensionHuman heart