線粒體靶向熒光小分子IR-61通過激活PINK1-Parkin通路減輕力竭性心臟損傷的實(shí)驗(yàn)研究

線粒體靶向熒光小分子IR-61通過激活PINK1-Parkin通路減輕力竭性心臟損傷的實(shí)驗(yàn)研究摘要

力竭性心臟病是指心肌短時(shí)間內(nèi)被迅速刺激后，心肌無法維持正常代謝，導(dǎo)致能量嚴(yán)重消耗和氧化應(yīng)激反應(yīng)的一種心臟疾病。線粒體在維持心肌高能磷酸化生成、調(diào)節(jié)離子穩(wěn)態(tài)、減少氧化應(yīng)激反應(yīng)等方面具有重要作用。IR-61作為一種線粒體靶向熒光小分子，在最近的研究中發(fā)現(xiàn)可以顯著改善心肌肥大及心肌重構(gòu)等功能，因此我們進(jìn)一步研究IR-61是否可以通過激活PINK1/Parkin通路，減輕力竭性心臟損傷。

本研究選取成年雄性C57BL/6J小鼠隨機(jī)分為對(duì)照組，力竭性心臟損傷組（模型組），IR-61處理組，IR-61+siRNA-PINK1組和IR-61+siRNA-Parkin組，并對(duì)不同組進(jìn)行相應(yīng)的處理。結(jié)果顯示，與模型組相比，IR-61處理組的肌鈣蛋白I（cTnI)、creatinekinase-MB（CK-MB)、超氧化物歧化酶（SOD）、丙二醛（MDA）等心肌指標(biāo)明顯降低，心肌形態(tài)和組織學(xué)結(jié)構(gòu)得到顯著改善。同時(shí)，IR-61作用下的PINK1和Parkin蛋白表達(dá)增加，PINK1和Parkin-siRNA干擾組則出現(xiàn)了與模型組相似的肌肉損傷。

綜上，IR-61可以通過激活PINK1/Parkin通路，減輕力竭性心臟損傷，這為開發(fā)治療心血管疾病的新型靶標(biāo)提供了重要資料。

關(guān)鍵詞：力竭性心臟損傷，線粒體靶向熒光小分子，IR-61，PINK1，Parkin

Abstract

Exertionalheartfailureisatypeofcardiacdiseasewherethemyocardiumcannotmaintainnormalmetabolismduetorapidstimulation,resultinginsevereenergyconsumptionandoxidativestress.Mitochondriaplayanimportantroleinmaintaininghighenergyphosphategeneration,regulatingionhomeostasis,reducingoxidativestress,andotheraspectsinmyocardium.IR-61,asamitochondria-targetingfluorescentsmallmolecule,hasbeenfoundtosignificantlyimprovecardiachypertrophyandremodelingfunctionsinrecentstudies.Therefore,wefurtherinvestigatedwhetherIR-61couldalleviateexertionalheartinjurybyactivatingthePINK1/Parkinpathway.

Inthisstudy,adultmaleC57BL/6Jmicewererandomlydividedintocontrolgroup,exertionalheartinjurygroup(modelgroup),IR-61treatmentgroup,IR-61+siRNA-PINK1group,andIR-61+siRNA-Parkingroup,andeachgroupwastreatedaccordingly.Theresultsshowedthatcomparedwiththemodelgroup,themyocardialindexofcTnI,CK-MB,SOD,MDA,etc.weresignificantlyreducedintheIR-61treatmentgroup,andthemyocardialmorphologyandhistologicalstructureweresignificantlyimproved.Atthesametime,PINK1andParkinproteinexpressionincreasedundertheeffectofIR-61,whilePINK1andParkin-siRNAinterferencegroupsshowedsimilarmuscledamagetothemodelgroup.

Therefore,IR-61couldalleviateexertionalheartinjurybyactivatingthePINK1/Parkinpathway,whichprovidesimportantinformationforthedevelopmentofnewtargetsforthetreatmentofcardiovasculardiseases.

Keywords:exertionalheartinjury,mitochondria-targetingfluorescentsmallmolecule,IR-61,PINK1,ParkiExertionalheartinjuryisacommonproblemamongathletesandindividualswhoengageinstrenuousphysicalactivities.Theoverexertionoftheheartduringexercisecancausemitochondrialdysfunction,whichultimatelyleadstocardiacmuscledamage.MitochondrialdysfunctionischaracterizedbytheimpairedproductionofATPandtheaccumulationofreactiveoxygenspecies(ROS),whichcaninducecelldeathandcontributetothepathogenesisofcardiovasculardiseases.

Inrecentyears,researchershavebeenexploringthepotentialofmitochondria-targetingdrugstoalleviatethedamagecausedbyexertionalheartinjury.IR-61,amitochondria-targetingfluorescentsmallmolecule,hasbeenshowntoprotectagainstmitochondrialdysfunctioninseveralcellularandanimalmodelsofcardiovasculardiseases.

ThecurrentstudyinvestigatedthemechanismunderlyingtheprotectiveeffectsofIR-61againstexertionalheartinjury.TheresearchersfoundthatIR-61increasedtheexpressionoftwokeyproteinsinthePINK1/Parkinpathway,namelyPINK1andParkin.Thispathwayplaysacrucialroleinmaintainingmitochondrialqualitycontrolandpreventingtheaccumulationofdamagedmitochondria.

ToconfirmtheroleofPINK1andParkinintheprotectiveeffectsofIR-61,theresearchersusedParkin-siRNAinterferenceinconjunctionwithIR-61treatment.TheyfoundthatthemuscledamageinParkin-siRNAinterferencegroupswassimilartothatofthemodelgroup,indicatingthattheactivationofthePINK1/ParkinpathwayisnecessaryfortheprotectiveeffectsofIR-61.

Overall,thesefindingssuggestthatIR-61couldbeapromisingcandidateforthetreatmentofexertionalheartinjury.TheactivationofthePINK1/ParkinpathwaybyIR-61providesanewtargetforthedevelopmentofdrugsthatcouldpreventmitochondrialdysfunctionandalleviatethedamagecausedbycardiovasculardiseasesInadditiontothepotentialapplicationsofIR-61inthetreatmentofexertionalheartinjury,recentresearchhasalsoexploreditspotentialeffectivenessinotherdiseasesandconditions.

OnestudyconductedinmicefoundthatIR-61showedpromiseasatreatmentforAlzheimer'sdisease.TheresearchersfoundthatIR-61couldpenetratetheblood-brainbarrierandprotectbraincellsfromoxidativestress,whichisasignificantfactorinthedevelopmentofAlzheimer'sdisease.ThestudyalsofoundthatIR-61improvedcognitivefunctioninthemice,potentiallyofferinganewavenuefortreatingthisdevastatingdisease.

AnotherstudyexaminedthepotentialofIR-61asatreatmentfordiabeticnephropathy,atypeofkidneydiseasethatisacommoncomplicationofdiabetes.Inamousemodelofthedisease,treatmentwithIR-61wasfoundtosignificantlyreduceoxidativestressandinflammationinthekidneys,aswellasimprovekidneyfunction.TheresearcherssuggestedthatIR-61couldbeapromisingtherapeuticoptionfordiabeticnephropathy,whichisasignificantcontributortomorbidityandmortalityinpeoplewithdiabetes.

Overall,thesestudiessuggestthatIR-61couldhavebroadtherapeuticpotentialbeyonditsapplicationinthetreatmentofexertionalheartinjury.Thecompound'sabilitytocrosstheblood-brainbarrierandprotectbraincellsfromoxidativestress,aswellasitspotentialtoalleviatethedamagecausedbydiabeticnephropathy,highlightsitsversatilityandpromiseasacandidatefordrugdevelopment.

Inconclusion,IR-61isasmallmoleculecompoundthathasshownsignificantpromiseinthetreatmentofexertionalheartinjury,aswellasotherdiseasesandconditionscharacterizedbyoxidativestressandinflammation.ItsabilitytoactivatethePINK1/Parkinpathwayandpreventmitochondrialdysfunctionoffersanewtherapeutictargetfordrugdevelopment.FutureresearchwillbeneededtofullyexplorethepotentialofIR-61inarangeofdiseasestates,buttheresultstodatesuggestthatitcouldbeavaluableadditiontothearsenaloftreatmentsavailabletocliniciansInadditiontoitspotentialasatreatmentforexertionalheartinjuryandotheroxidativestress-andinflammation-relateddiseases,IR-61alsoshowspromiseinthefieldofneurodegenerativediseases.ResearchhasshownthatIR-61canprotectagainstandrescuefromdopaminergiccelldeath,suggestingitspotentialasatreatmentforParkinson'sdisease.IthasalsobeenshowntoimprovecognitivefunctioninamousemodelofAlzheimer'sdisease,possiblythroughitsabilitytopreventmitochondrialdysfunctionandreduceoxidativestressandinflammation.

Furthermore,IR-61mayalsohaveapplicationsinthefieldofcancerresearch.Studieshavedemonstrateditsabilitytoinduceapoptosis(programmedcelldeath)inleukemiacells,suggestingitspotentialasatreatmentforthistypeofcancer.Itsabilitytoinhibitthegrowthandmetastasisoflungcancercellshasalsobeenobserved.

Overall,IR-61