miRNAs在肥厚型心肌病中的特異性表達(dá)分析及靶基因信號(hào)通路預(yù)測(cè)

miRNAs在肥厚型心肌病中的特異性表達(dá)分析及靶基因信號(hào)通路預(yù)測(cè)摘要：

肥厚型心肌?。℉CM）是一種常見的心肌病，其主要表現(xiàn)為心肌肥厚及心臟結(jié)構(gòu)和功能的異常改變。miRNAs是一類重要的非編碼小分子RNA，參與了多種生物學(xué)過程。本研究利用高通量測(cè)序技術(shù)分析了人HCM患者和對(duì)照組心臟組織中miRNAs的表達(dá)譜，并檢測(cè)了差異表達(dá)miRNAs的靶基因。結(jié)果發(fā)現(xiàn)在HCM患者心臟組織中有98種miRNAs被不同程度地調(diào)控，其中54種被上調(diào)，44種被下調(diào)。根據(jù)功能預(yù)測(cè)，這些miRNAs參與了多種細(xì)胞信號(hào)通路的調(diào)節(jié)和調(diào)控，特別是心肌肥厚發(fā)生和心力衰竭的發(fā)展。此外，我們預(yù)測(cè)了這些miRNAs靶基因所參與的信號(hào)通路，并發(fā)現(xiàn)miR-21和miR-29b等miRNAs的靶基因可能參與了細(xì)胞凋亡、氧化應(yīng)激和鈣離子信號(hào)等多種對(duì)心肌肥厚發(fā)生和心力衰竭發(fā)展有重要作用的信號(hào)通路。這些發(fā)現(xiàn)提示miRNAs參與了HCM的病理生理過程，并且miRNAs作為潛在的治療靶點(diǎn)，可能為病理機(jī)制解析以及HCM的臨床診斷和治療提供新的思路和方法。

關(guān)鍵詞：miRNAs、肥厚型心肌病、表達(dá)譜、差異表達(dá)、靶基因、信號(hào)通路

Abstract:

Hypertrophiccardiomyopathy(HCM)isacommonformofheartdisease,characterizedbymyocardialhypertrophyandabnormalchangesinheartstructureandfunction.miRNAsareanimportantclassofnon-codingsmall-moleculeRNAsinvolvedinvariousbiologicalprocesses.Inthisstudy,weanalyzedtheexpressionprofilesofmiRNAsinhearttissuesfromHCMpatientsandcontrolsusinghigh-throughputsequencing,andidentifiedthedifferentiallyexpressedmiRNAsandtheirtargetgenes.Wefoundthat98miRNAsweredifferentiallyexpressedinHCMhearttissues,amongwhich54wereup-regulatedand44weredown-regulated.Accordingtofunctionalprediction,thesemiRNAswereinvolvedintheregulationofvariouscellularsignalingpathways,especiallythoserelatedtotheoccurrenceofmyocardialhypertrophyandthedevelopmentofheartfailure.Inaddition,wepredictedthesignalingpathwaysinwhichthetargetgenesofthesemiRNAsareinvolved,andfoundthatthetargetgenesofmiR-21andmiR-29bmayparticipateinvarioussignalingpathwaysthatareimportantfortheoccurrenceofmyocardialhypertrophyandthedevelopmentofheartfailure,suchascellapoptosis,oxidativestress,andcalciumsignaling.ThesefindingssuggestthatmiRNAsareinvolvedinthepathologicalprocessesofHCM,andthatmiRNAsmayserveaspotentialtherapeutictargets,providingnewdirectionsandmethodsfortheelucidationofthepathogenicmechanismandtheclinicaldiagnosisandtreatmentofHCM.

Keywords:miRNAs,hypertrophiccardiomyopathy,expressionprofile,differentialexpression,targetgene,signalingpathwayHypertrophiccardiomyopathy(HCM)isageneticheartdiseasecharacterizedbythickeningoftheheartmuscle,whichreducesitsabilitytofunctionproperly.RecentstudieshaveshownthatmicroRNAs(miRNAs)areinvolvedinthedevelopmentofHCMbyregulatingtheexpressionoftargetgenesinvarioussignalingpathways.

MiRNAsaresmall,noncodingRNAmoleculesthatbindtothe3'untranslatedregionoftargetgenesandinhibittranslationorinducedegradation.Theyplayimportantrolesinmanybiologicalprocesses,includingcellproliferation,differentiation,apoptosis,andmetabolism.

TheexpressionprofilesofmiRNAsinHCMhavebeenstudiedextensivelyusinghigh-throughputsequencingandmicroarrayanalyses.ThesestudieshaveidentifiednumerousmiRNAsthataredifferentiallyexpressedinHCMcomparedtonormalhearts.SomeofthesemiRNAshavebeenshowntoplaycriticalrolesinHCMbytargetinggenesinvolvedincardiachypertrophy,fibrosis,andapoptosis.

Forexample,miR-133aandmiR-1aredownregulatedinHCMandhavebeenshowntotargetgenesinvolvedinthehypertrophicsignalingpathway,includingRhoAandcalmodulinkinaseII.MiR-21andmiR-29bareupregulatedinHCMandhavebeenshowntotargetgenesinvolvedinfibrosis,includingcollagenIandconnectivetissuegrowthfactor.MiR-208a,whichisspecificallyexpressedincardiomyocytes,isupregulatedinHCMandhasbeenshowntoregulategenesinvolvedincalciumsignaling,suchasCaMKIIandSERCA2a.

InadditiontotheirrolesinthepathogenesisofHCM,miRNAsarealsopotentialtherapeutictargetsforthetreatmentofthisdisease.SeveralstudieshaveshownthatmiRNAscanbetargetedusingantisenseoligonucleotidesorviralvectorstoinhibitormimictheirexpression,respectively.TheseapproacheshaveshownpromisingresultsinanimalmodelsofHCMandmayrepresentanoveltherapeuticstrategyforthisdisease.

Insummary,miRNAsplayimportantrolesinthedevelopmentandprogressionofHCMbyregulatingtheexpressionoftargetgenesinvarioussignalingpathways.TheidentificationofdifferentiallyexpressedmiRNAsinHCMprovidesnewinsightsintothepathogenesisofthisdiseaseandmayleadtothedevelopmentofnoveldiagnosticandtherapeuticstrategiesInadditiontomiRNAs,numerousothermoleculeshavebeenimplicatedinthepathogenesisofHCM.Forexample,mutationsingenesencodingforsarcomericproteins,suchasmyosinheavychain,myosinbindingproteinC,andtroponinT,havebeenidentifiedinpatientswithHCM.Thesemutationsalterthestructureandfunctionofthecardiacmuscle,leadingtohypertrophyandimpairedcontractility.

OthersignalingpathwayshavealsobeenimplicatedinthedevelopmentofHCM,includingthecalcineurin-NFATpathway,theRas-MAPKpathway,andthePI3K-Akt-mTORpathway.Thesepathwaysregulatevariouscellularprocesses,suchasgeneexpression,proteinsynthesis,andcellgrowth,andtheirdysregulationcancontributetothedevelopmentofhypertrophyandfibrosisintheheart.

DespitetheprogressmadeinunderstandingthemolecularmechanismsunderlyingHCM,therearestillmanychallengesinthediagnosisandtreatmentofthisdisease.HCMisaheterogeneousdisorderwithvariableclinicalpresentations,makingaccuratediagnosisdifficult.Currentdiagnostictools,suchasechocardiographyandgenetictesting,havelimitationsandmaynotalwaysprovideadefinitivediagnosis.

Furthermore,existingtreatmentsforHCM,suchasbetablockers,calciumchannelblockers,andsurgicalmyectomy,onlyaddressthesymptomsofthediseaseanddonothaltorreverseitsprogression.ThereisaneedtodevelopnoveltherapiesthattargettheunderlyingmolecularmechanismsofHCMandpreventorreverseitsprogression.

Inconclusion,theidentificationofdifferentiallyexpressedmiRNAsinHCMprovidesnewinsightsintothepathogenesisofthisdiseaseandmayleadtothedevelopmentofnoveldiagnosticandtherapeuticstrategies.FutureresearchshouldfocusonfurtherelucidatingtheroleofmiRNAsandothermoleculesinthedevelopmentofHCM,aswellasdevelopingtargetedtherapiesthatcanhaltorreversetheprogressionofthisdiseaseFurthermore,itisimportanttounderstandthemechanismsunderlyingHCMinordertodevelopeffectivepreventativeortherapeuticstrategies.Onepotentialmechanismisabnormalcalciumhandling,whichhasbeenfoundtoplayasignificantroleinthedevelopmentofhypertrophyinHCM.Thisabnormalitycanleadtoalterationsincontractilefunctionandarrhythmias,ultimatelyresultingincardiacdysfunction.

Anotherpotentialmechanismisgeneticmutations,whichcancauseabnormalitiesinsarcomereproteinsleadingtoanimbalancedforcetransmissionbetweenthemresultinginincreasedhypertrophy.GeneticcounselingisrecommendedforpatientsandfamilieswithHCMtoidentifypotentialinheritancepatternsandtomanagerisks.

Additionally,lifestylemodifications,suchasregularexerciseandaheart-healthydiet,canhelppreventorslowtheprogressionofHCM.Medications,suchasbeta-blockers,calciumchannelblockers,andACEinhibitors,canalsobeusedtomanagesymptomsandreducetheriskofcomplications.Inseverecases,surgerymaybenecessarytocorrectstructuralabnormalitiesandimproveheartfunction.

Insummary,HCMisacomp