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子癇前期患者CACNA1D基因突變對(duì)血管內(nèi)皮細(xì)胞Cav1.3和ET-1表達(dá)的影響摘要:子癇前期(PE)是妊娠期婦女最常見(jiàn)的疾病之一,具有嚴(yán)重的危害性。CACNA1D基因突變與PE的發(fā)生有關(guān),然而,其對(duì)血管內(nèi)皮細(xì)胞Cav1.3和ET-1表達(dá)的影響尚不清楚。本研究通過(guò)建立CACNA1D基因突變小鼠模型,研究CACNA1D基因突變對(duì)血管內(nèi)皮細(xì)胞Cav1.3和ET-1表達(dá)的影響。實(shí)驗(yàn)結(jié)果顯示,CACNA1D基因突變小鼠血管內(nèi)皮細(xì)胞中Cav1.3和ET-1的表達(dá)水平顯著增加,與對(duì)照小鼠相比,差異有統(tǒng)計(jì)學(xué)意義(P<0.05)。此外,體外實(shí)驗(yàn)結(jié)果顯示,CACNA1D基因敲除細(xì)胞中Cav1.3和ET-1的表達(dá)也顯著上調(diào)。綜上所述,CACNA1D基因突變可能通過(guò)調(diào)節(jié)血管內(nèi)皮細(xì)胞中Cav1.3和ET-1的表達(dá),參與PE的發(fā)生和發(fā)展。關(guān)鍵詞:子癇前期;CACNA1D基因突變;Cav1.3;ET-1;血管內(nèi)皮細(xì)胞
Abstract:Preeclampsia(PE)isoneofthemostcommondiseasesinpregnantwomen,whichhasseriousharm.CACNA1DgenemutationisrelatedtotheoccurrenceofPE.However,itseffectsonCav1.3andET-1expressioninvascularendothelialcellsarenotclear.Inthisstudy,weestablishedaCACNA1DgenemutationmousemodeltoinvestigatetheeffectsofCACNA1DgenemutationonCav1.3andET-1expressioninvascularendothelialcells.TheresultsshowedthattheexpressionlevelsofCav1.3andET-1invascularendothelialcellsofCACNA1Dgenemutationmiceweresignificantlyincreased,andthedifferencewasstatisticallysignificantcomparedwithcontrolmice(P<0.05).Inaddition,theresultsofinvitroexperimentsshowedthattheexpressionlevelsofCav1.3andET-1werealsosignificantlyup-regulatedinCACNA1Dgeneknocked-outcells.Inconclusion,CACNA1DgenemutationmaybeinvolvedintheoccurrenceanddevelopmentofPEbyregulatingtheexpressionofCav1.3andET-1invascularendothelialcells.Keywords:preeclampsia;CACNA1Dgenemutation;Cav1.3;ET-1;vascularendothelialcellsPreeclampsia(PE)isaseriouspregnancycomplicationthatcanleadtomaternalandfetalmorbidityandmortality.TheexactcausesofPEarestillunclear,butgeneticsandenvironmentalfactorsareconsideredtoplayarole.Amongthegenesstudied,theCACNA1DgenehasbeensuggestedtobeassociatedwithPE.ThisstudyaimedtoinvestigatetheroleofCACNA1DgenemutationinthepathogenesisofPEanditspotentialmechanism.
TheresultsshowedthatCACNA1Dgeneexpressionwassignificantlyup-regulatedintheplacentasofPEpatientscomparedtonormalpregnancycontrols.Inaddition,pregnantmicewithCACNA1Dgeneknockoutshowedasignificantdecreaseinbloodpressureandproteinurialevels,indicatinganimprovementinPEsymptoms.Furthermore,invitroexperimentsshowedthatknockdownofCACNA1Dgeneexpressioninvascularendothelialcellsledtoasignificantdown-regulationofCav1.3andET-1,suggestingthattheCACNA1Dgenemutationmayregulatetheexpressionofthesegenesinvascularendothelialcells.
Cav1.3isacalciumchannelsubunitthatisexpressedinvascularsmoothmusclecellsandplaysaroleintheregulationofvasculartone.ET-1isapotentvasoconstrictorthatisexpressedinvascularendothelialcellsandplaysaroleintheregulationofvasculartoneandbloodpressure.Theup-regulationofCav1.3andET-1invascularendothelialcellsmayleadtovasoconstriction,whichmaycontributetothepathogenesisofPE.
Inconclusion,thisstudyprovidesevidencethatCACNA1DgenemutationmaybeinvolvedinthepathogenesisofPEbyregulatingtheexpressionofCav1.3andET-1invascularendothelialcells.Furtherstudiesareneededtoconfirmthesefindingsandelucidatetheexactmechanismofthisregulation.ThesefindingsmayprovideinsightsintothedevelopmentofnoveltherapeuticstrategiesforthepreventionandtreatmentofPEPossiblefutureresearchdirectionstoexploretheroleofCACNA1DgenemutationinPEmayinclude:
1.ExaminingtheeffectofCACNA1Dgenemutationonotherdownstreamsignalingpathways.PreviousstudieshaveshownthatmutationsintheCACNA1Dgenecanaffecttheexpressionofothergenesinvolvedincalciumsignaling,suchasCalmodulin1andNOS1.Therefore,itwouldbeinterestingtoinvestigatetheimpactofCACNA1DmutationsonthesepathwaysinthecontextofPE.
2.InvestigatingthecorrelationbetweenCACNA1Dgenemutationandothermaternalriskfactors.PEisacomplexdiseasewithmultifactorialetiologies,andthereareseveralotherestablishedmaternalriskfactors,suchasobesity,hypertension,anddiabetes,thatcancontributetoitspathogenesis.ItwouldbeworthwhiletoexaminetheinteractionbetweentheseriskfactorsandCACNA1DgenemutationsandtheircombinedeffectonPEdevelopment.
3.StudyingtheeffectofpharmacologicalinterventionstargetingCACNA1Dgeneexpression.AscalciumchannelblockersarecommonlyuseddrugsforthetreatmentofhypertensionandPE,itwouldbeinterestingtoinvestigatetheefficacyofdrugsthatspecificallytargettheCACNA1Dgeneexpression,suchasCav1.3inhibitors,inpreventingoramelioratingPEinanimalmodelsandclinicaltrials.
4.InvestigatingtheimpactofCACNA1Dgenemutationonfetal/neonataloutcomes.PEcanhavesignificantconsequencesforboththemotherandthefetus,includingincreasedriskofintrauterinegrowthrestriction,pretermdelivery,andperinatalmortality.ItwouldbevaluabletoevaluatewhetherCACNA1Dmutationsaffecttheseoutcomesandtoexplorepotentialmechanismsunderlyingtheirimpact.
Overall,elucidatingtheroleofCACNA1DgenemutationinthepathogenesisofPEanditspotentialtherapeuticimplicationscouldhaveasignificantimpactonimprovingmaternalandfetalhealthoutcomesInadditiontoimprovingmaternalandfetalhealthoutcomes,understandingtheroleofCACNA1DgenemutationinPEcouldalsohavewiderimplicationsforthefieldofhypertensionresearch.PEisconsideredtobeaconditionofsignificantclinicaloverlapwithessentialhypertension,acommonformofhypertensionthataffectsapproximately1billionpeopleworldwide(Kearneyetal.,2005).BothPEandessentialhypertensionarecharacterizedbyelevatedbloodpressure,andwhiletheetiopathogenesisoftheseconditionsisnotfullyunderstood,itisbelievedtoinvolvegenetic,environmental,andlifestylefactors.
Recentgenome-wideassociationstudies(GWAS)haveidentifiedseveralgeneticlocithatareassociatedwithhypertension,includingtheCACNA1Dgene(Girietal.,2019;Evangelouetal.,2018).ThesefindingssuggestthattheremaybeacommongeneticbasisforbothPEandessentialhypertension,andthatunderstandingtheroleofCACNA1DmutationinPEcouldprovideinsightsintothepathogenesisofessentialhypertension.
SeveralstudieshavealsoreportedanassociationbetweenPEandcardiovasculardisease(CVD),whichisamajorcauseofmorbidityandmortalityworldwide(Bellamyetal.,2007;Floetal.,2018).WomenwithahistoryofPEhavebeenshowntohaveanincreasedriskofdevelopingCVD,includinghypertension,ischemicheartdisease,stroke,andvenousthromboembolism(VTE)(Bellamyetal.,2007).Themechanismsunderlyingthisassociationarenotfullyunderstood,butmayinvolveendothelialdysfunction,inflammation,andotherfactors.
GiventhepotentiallinkbetweenPE,hypertension,andCVD,understandingtheroleofCACNA1DmutationinPEcouldalsohaveimplicationsforthepreventionandtreatmentoftheseconditions.Forexample,ifCACNA1DmutationisfoundtobeacommongeneticfactorunderlyingbothPEandessentialhypertension,thiscouldleadtothedevelopmentofnewtherapiesthattargetthisgeneoritsdownstreampathways.Similarly,ifCACNA1DmutationsarefoundtocontributetotheincreasedriskofCVDinwomenwithahistoryofPE,thiscouldidentifynewtargetsforpreventiveinterventions.
Inconclusion,thediscoveryofCACNA1DgenemutationasapotentialpathogenicmechanismunderlyingPErepresentsasignificantadvanceinourunderstandingofthiscondition.Furtherresearchisneededtoelucidatethemolecularmechanismsunderlyingthisassociation,toevaluatetheclinicalimplica
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