miR-143ActivationRegulatesSmoothMuscleandEndothelialCellCrosstalkinPulmonaryArterialHypertensionLinDeng#1,FranciscoJ.Blanco#1,HannahStevens1,RuifangLu1,6,AxelleCaudrillier1,MartinMcBride1,JohnDMcClure1,JennyGrant1,MatthewThomas2,7,MariaFrid3,KurtStenmark3,KevinWhite1,8,AnitaG.Seto4,NicholasW.Morrell5,AngelaCBradshaw1,MargaretR.MacLean1,andAndrewH.Baker11InstituteofCardiovascularandMedicalSciences,UniversityofGlasgow,Glasgow,G128TA,UK2NovartisInstitutesforBioMedicalResearch,HorshamUK3DivisionofCriticalCareMedicine/CardiovascularPulmonaryResearchLaboratories,DepartmentofPediatricsandMedicine,UniversityofColoradoDenver,Aurora,CO80045,USA4MiRagenTherapeutics,Inc,Boulder,CO5DivisionofRespiratoryMedicine,DepartmentofMedicine,Addenbrooke’sHospital,UniversityofCambridgeSchoolofClinicalMedicine,Cambridge,CB20QQ,UK6King’sBritishHeartFoundationCentre,King’sCollegeLondon,125ColdharbourLane,LondonSE59NU,UnitedKingdom7AstraZenecaR&DMölndal,R&D|Respiratory,InflammationandAutoimmunity(RIA)InnovativeMedicines,BuildingAC461,SE-43183Mölndal,Sweden8NovartisInstitutesforBioMedicalResearch,Inc.,250MassachusettsAvenue,Cambridge,MA02139,UnitedStates#Theseauthorscontributedequallytothiswork.AbstractRationale—ThepathogenesisofPAHremainsunclear.ThefourmicroRNAsrepresentingthemiR-143andmiR-145stemloopsaregenomicallyclustered.Objective—ToelucidatethetranscriptionalregulationofthemiR-143/145cluster,andtheroleofmiR-143inPAH.MethodsandResults—WeidentifiedthepromoterregionthatregulatesmiR-143/145miRNAexpressioninpulmonaryarterysmoothmusclecells(PASMCs).WemappedPAH-relatedsignallingpathways,includingestrogensreceptor(ER),liverXfactor/retinoicXreceptor(LXR/RXR),TGF-β(Smads),andhypoxia(HRE)thatregulatedlevelsofallpri-miRstemlooptranscriptionandresultingmiRNAexpression.WeobservedthatmiR-143-3pisselectivelyAddresscorrespondenceto:Dr.AndrewH.Baker,InstituteofCardiovascularandMedicalSciences,UniversityofGlasgow,Glasgow,G128TA,UK.TelNo:+4401413301977,FaxNo:+4401413303360,Andrew.H.Baker@glasgow....
