NOX4基因缺失對內(nèi)皮功能紊亂和動(dòng)脈粥樣硬化的影響_第1頁
NOX4基因缺失對內(nèi)皮功能紊亂和動(dòng)脈粥樣硬化的影響_第2頁
NOX4基因缺失對內(nèi)皮功能紊亂和動(dòng)脈粥樣硬化的影響_第3頁
NOX4基因缺失對內(nèi)皮功能紊亂和動(dòng)脈粥樣硬化的影響_第4頁
NOX4基因缺失對內(nèi)皮功能紊亂和動(dòng)脈粥樣硬化的影響_第5頁
已閱讀5頁，還剩13頁未讀， 繼續(xù)免費(fèi)閱讀

下載本文檔

版權(quán)說明：本文檔由用戶提供并上傳，收益歸屬內(nèi)容提供方，若內(nèi)容存在侵權(quán)，請進(jìn)行舉報(bào)或認(rèn)領(lǐng)

文檔簡介

NADPHoxidase4protectsagainstdevelopmentofendothelialdysfunctionandatherosclerosisinLDLreceptordeficientmiceEuropeanHeartJournalNovember17,2015

IntroductionEndothelialdysfunctionisanearlyeventinatherosclerosisthatprecedesclinicalsymptoms.TheroleofdifferentNoxisoformsincardiovascularphysiologyandpathophysiologyiscontroversial.IncreasedformationofsuperoxideanionsbyNox1,2,and5reducesNOavailabilityandcanpromoteendothelialdysfunction.recentevidencesupportsavasoprotectiveroleofH2O2producedbyNox4.Therefore,weanalysedtheimpactofgeneticdeletionofNox4onendothelialdysfunctionandatherosclerosisintheLdlr-/-model.Results1.Nox4-/-Ldlr-/-micedevelopendothelialdysfunction.

2.Nox4-/-Ldlr-/-miceonhigh-fatdietdevelopincreasedatherosclerosis.3.LossofNox4-derivedH2O2couldbepartiallycompensatedforbynNOSupregulation4.SaphenousarteryofNox4-/-miceshowimpairedflow-mediateddilationinvivo.1.Nox4-/-Ldlr-/-micedevelopendothelialdysfunction(A)Concentration–responsecurveforAchinaorticsegmentsof10-week-oldwild-type,Ldlr-/-,Nox4-/-,andNox4-/-/Ldlr-/-mice(n≥10)precontractedwithphenylephrine.(B)Maximaleffectof30mmol/LAChonaorticsegmentsofwild-type,Ldlr-/-,Nox4-/-,andNox4-/-/Ldlr-/-mice(n≥10).(C)Concentration–responsecurvesforsodiumnitroprussideinaorticsegmentsbetweenthestrainsofmice.1.Nox4-/-Ldlr-/-micedevelopendothelialdysfunctionConcentration–responsecurveforacetylcholineinaorticsegmentsof10-week-oldwild-typeandLdlr-/-micewithcatalase.1.Nox4-/-Ldlr-/-micedevelopendothelialdysfunctionConcentration–responsecurveforacetylcholineinaorticsegmentsof10-week-oldwild-typeandLdlr-/-micewithpaxilline.1.Nox4-/-Ldlr-/-micedevelopendothelialdysfunction(H)AmplexredassayforH2O2generationofAortathoracalissegmentsofwild-type,

Ldlr-/-,Nox4-/-,andNox4-/-/Ldlr-/-

.H2O2formationwasmeasuredasthecatalase-sensitivepartofthesignal(a.u.:arbitraryunits).(IandJ)Real-timepolymerasechainreactionofmurineaortafromwild-type,Ldlr-/-,Nox4-/-,andNox4-/-/Ldlr-/-

mice.1.Nox4-/-Ldlr-/-micedevelopendothelialdysfunction(K)WesternblotanalysisofpAKT1inhumanumbilicalveinendothelialcellstransducedwithshControlorshNOX4for48h.Cellswereeitherkeptunderstaticconditionsorexposedtolaminarshearstress(30dyn/cm2)for5min.(L)Real-timepolymerasechainreactionofNOX4inhumanumbilicalveinendothelialcells.Cellsweretransducedfor72hwithshControlorshNOX4.2.Nox4-/-/Ldlr-/-miceonhigh-fatdietdevelopincreasedatherosclerosis

(A)Atheroscleroticplaqueburden:PlaqueareaintheaorticarchofNox4-/-/Ldlr-/-micewassignificantlyhigher.(B)Galectin-3stainingofaorticarchsectionsofLdlr--andNox4--/Ldlr-/-mice.(C)CollagencontentbySiriusRedstainingwassignificantlyincreasedinNox4-/-/Ldlr-/-mice3.CompensationofH2O2releaseinolderNox4-/-micedecreasedaorticH2O2(Aortathoracalis)levelsinyoungNox-/-micewererestoredtolevelsofwild-typemiceat26weeksofage.

aroleofnNOSaspotentialsourceofH2O2.3.CompensationofH2O2releaseinolderNox4-/-mice

nNOSmRNAexpressionwassignificantlyincreasedinaortasof26-week-oldbutnot10-week-oldNox4-/-mice3.CompensationofH2O2releaseinolderNox4-/-miceE：Aorticendothelialfunctionof26-week-oldNox4-/-wasnotaltered.F：However,NOavailabilityseemedtobedecreasedinaorticsegmentsofNox42/2mice.ThesemiceshowedatrendtodecreasedL-NAME-inducedendothelium-dependentconstriction.AlthoughexvivoanalysisofvascularfunctionintheaortaofNox4-/-miceshowednodifferenceinendothelium-dependentrelaxationcomparedwithwild-typemice,FMDinsaphenousarteryintheNox4-/-micewassignificantlyreduced.Thissupportsamuchhighersensitivityoftheinvivomethodtoobjectifyalterationsinvesselfunction.4.SaphenousarteryofNox4-/-miceshowimpairedFMDinvivoNox42/2miceshowalteredFMDinvivo.(A)OCTofArteriasaphenaandevaluationofimagesof26-week-old(A)wild-type,(B)Ldlr-/-,and(C)Nox4-/-miceunderrestingcondition,FMDandafterapplicationofSNP.significantincreaseinvesseldiameterduetoFMDinWTmice,whilenosignificantincreaseinvesseldiameterafterclampreleasecouldbedetectedineitherNox4-/-orLdlr-/-mice.SNPcausedsimilarincreasesofvesseldiameter.4.SaphenousarteryofNox4-/-miceshow

impairedflow-mediateddilationinvivoOCTscanoftheArteriasaphenaof26-week-oldWT,Ldlr-/-,andNox4-/-miceshowingtheprocessofFMDduring10minafterocclusion.Discussion1.Nox4→H2O2→pAKT→eNOS→NO↑→vasodilation2.H2O2mightactasanEDHF(內(nèi)皮超極化因子)inmiceandman.H2O2（EDHF）→BKCa↑→hyperpolarizedmembrane→vasodilation3.InflammationmarkerGalectin-3andcollagencontentwasalsoincreasedinNox4-/-/Ldlr-/-comparedwithLdlr2/2mice.4.olderNox4-/-mice：代償性nNOS↑→H2O2↑5.amuchhighersensitivityoftheinvivomethodtoobjectifyalterationsinvesselfunction.ConclusionsNox4playsanimportantroleinmaintainingendothe

溫馨提示

  • 1. 本站所有資源如無特殊說明，都需要本地電腦安裝OFFICE2007和PDF閱讀器。圖紙軟件為CAD,CAXA,PROE,UG,SolidWorks等.壓縮文件請下載最新的WinRAR軟件解壓。
  • 2. 本站的文檔不包含任何第三方提供的附件圖紙等，如果需要附件，請聯(lián)系上傳者。文件的所有權(quán)益歸上傳用戶所有。
  • 3. 本站RAR壓縮包中若帶圖紙，網(wǎng)頁內(nèi)容里面會(huì)有圖紙預(yù)覽，若沒有圖紙預(yù)覽就沒有圖紙。
  • 4. 未經(jīng)權(quán)益所有人同意不得將文件中的內(nèi)容挪作商業(yè)或盈利用途。
  • 5. 人人文庫網(wǎng)僅提供信息存儲(chǔ)空間，僅對用戶上傳內(nèi)容的表現(xiàn)方式做保護(hù)處理，對用戶上傳分享的文檔內(nèi)容本身不做任何修改或編輯，并不能對任何下載內(nèi)容負(fù)責(zé)。
  • 6. 下載文件中如有侵權(quán)或不適當(dāng)內(nèi)容，請與我們聯(lián)系，我們立即糾正。
  • 7. 本站不保證下載資源的準(zhǔn)確性、安全性和完整性, 同時(shí)也不承擔(dān)用戶因使用這些下載資源對自己和他人造成任何形式的傷害或損失。

評論

0/150

提交評論