线粒体靶向荧光小分子IR-61通过激活PINK1-Parkin通路减轻力竭性心脏损伤的实验研究

线粒体靶向荧光小分子IR-61通过激活PINK1-Parkin通路减轻力竭性心脏损伤的实验研究摘要

力竭性心脏病是指心肌短时间内被迅速刺激后，心肌无法维持正常代谢，导致能量严重消耗和氧化应激反应的一种心脏疾病。线粒体在维持心肌高能磷酸化生成、调节离子稳态、减少氧化应激反应等方面具有重要作用。IR-61作为一种线粒体靶向荧光小分子，在最近的研究中发现可以显著改善心肌肥大及心肌重构等功能，因此我们进一步研究IR-61是否可以通过激活PINK1/Parkin通路，减轻力竭性心脏损伤。

本研究选取成年雄性C57BL/6J小鼠随机分为对照组，力竭性心脏损伤组（模型组），IR-61处理组，IR-61+siRNA-PINK1组和IR-61+siRNA-Parkin组，并对不同组进行相应的处理。结果显示，与模型组相比，IR-61处理组的肌钙蛋白I（cTnI)、creatinekinase-MB（CK-MB)、超氧化物歧化酶（SOD）、丙二醛（MDA）等心肌指标明显降低，心肌形态和组织学结构得到显著改善。同时，IR-61作用下的PINK1和Parkin蛋白表达增加，PINK1和Parkin-siRNA干扰组则出现了与模型组相似的肌肉损伤。

综上，IR-61可以通过激活PINK1/Parkin通路，减轻力竭性心脏损伤，这为开发治疗心血管疾病的新型靶标提供了重要资料。

关键词：力竭性心脏损伤，线粒体靶向荧光小分子，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