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iabeticheartdisease(DHD)isadebilitatingmanifestationoftype2diabetes.ExercisehasbeenproposedasapotentialtherapyforDHD,althoughtheeffectivenessofexerciseinpreventingorreversingtheprogressionofDHDremainscontroversial.Cardiacfunctioniscriticallydependentonthepreservationofcoronaryvascularfunction.糖尿病性心脏病（DHD）是2型糖尿病的一种衰弱表现。运动被认为是一种潜在的治疗DHD的方法，尽管运动在预防或逆转DHD进展方面的有效性仍然存在争议。心脏功能的关键取决于冠状动脉血管功能的保存。Objective:Weaimedtoelucidatetheeffectivenessandmechanismsbywhichexercisefacilitatescoronaryandcardiac-protectionduringtheonsetandprogressionofDHD.我们旨在阐明运动促进DHD发病和发展过程中冠状动脉和心脏保护的有效性和机制。MethodsandResults
iabeticdb/dbandnon-diabeticmice,withorwithoutunderlyingcardiacdysfunction(16and8weeksold,respectively)weresubjectedtoeithermoderate-intensityexercise(MIE)orhigh-IE(HIE)foreightweeks.Subsequently,synchrotronmicroangiography,immunohistochemistry,Westernblot,andRT-PCRwereusedtoassesstime-dependentchangesincardiacandcoronarystructureandfunctionassociatedwithdiabetesandexercise,anddeterminewhetherthesechangesreflecttheobservedchangesincardiac-enrichedandvascular-enrichedmicroRNAs(miRNAs).Weshowthat,ifexerciseisinitiatedfrom8weeksofage,bothMIEandHIEpreventedtheonsetofcoronaryandcardiacdysfunction,apoptosis,fibrosis,microvascularrarefaction,anddisruptionofmiRNAsignaling,asseeninthenon-exerciseddiabeticmice.Conversely,thecardiovascularbenefitsofMIEwereabsentiftheexercisewasinitiatedafterthediabeticmicehadalreadyestablishedcardiacdysfunction(i.e.from16weeksofage).TheexperimentalsilencingorupregulationofmiRNA-activitysuggeststhemechanismunderpinningthecardiovascularbenefitsofexerciseweremediated,atleastinpart,throughtissue-specificmiRNAs.糖尿病db/db和非糖尿病小鼠（分别为16周和8周龄）接受中等强度运动（MIE）或高强度IE（HIE）8周。随后，采用同步辐射微血管成像、免疫组织化学、Westernblot和RT-PCR来评估与糖尿病和运动相关的心脏和冠状动脉结构和功能的时间依赖性变化，并确定这些变化是否反映了观察到的心肌富集和血管富集microRNAs（miRNAs）的变化。我们发现，如果从8周龄开始运动，MIE和HIE都能阻止冠状动脉和心脏功能不全、细胞凋亡、纤维化、微血管稀疏和miRNA信号中断的发生，正如在非运动糖尿病小鼠中所见。相反，如果运动是在糖尿病小鼠已经出现心脏功能障碍（即从16周龄开始）后开始的，那么MIE对心血管的益处就不存在了。miRNA-活性的实验性沉默或上调表明，运动对心血管有益的机制至少部分是通过组织特异性miRNA介导的。Conclusions:OurfindingsprovidethefirstexperimentalevidenceforthecriticalimportanceofearlyexerciseinterventioninamelioratingtheonsetandprogressionofDHD.Ourresultsalsosuggestthatthebeneficialeffectsofexercisearemediatedthroughthenormalizationofcardiovascular-enrichedmiRNAs,whicharedysregulatedinDHD.我们的研究结果为早期运动干预在改善DHD的发生和发展中的关键重要性提供了第一个实验证据。我们的结果还表明，运动的有益效果是通过心血管丰富的miRNAs的正常化而介导的，后者在DHD中调节失调。扫描
