NO与神经血管保护

JPhysiol589.17(2011)pp4137–4145

4137

SYMPOSIUMREVIEW

Neurovascularprotectionbyischaemictolerance:roleofnitricoxide

CostantinoIadecola,TimoKahles,EduardoF.GalloandJosefAnrather

DivisionofNeurobiology,DepartmentofNeurologyandNeuroscience,WeillCornellMedicalCollege,NewYork,NY10065,USA

TheJournalofPhysiology

AbstractNitricoxide(NO)hasemergedasakeymediatorinthemechanismsofischaemictoleranceinducedbyawidevarietyofpreconditioningstimuli.NOisinvolvedinthebrainprotectionthatdevelopseitherearly(minutes–hours)orlate(days–weeks)afterthepre-conditioningstimulus.However,thesourcesofNOandthemechanismsunderlyingtheprotectiveeffectsdiffersubstantially.WhileinearlypreconditioningNOisproducedbytheendothelialandneuronalisoformofNOsynthase,indelayedpreconditioningNOissynthesizedbytheinducibleor‘immunological’isoformofNOsynthase.Furthermore,inearlypreconditioning,NOactsthroughthecanonicalcGMPpathway,possiblythroughproteinkinaseGandopeningofmitochondrialKATPchannels.Inlatepreconditioning,theprotectionismediatedbyperoxynitriteformedbythereactionofNOwithsuperoxidederivedfromtheenzymeNADPHoxidase.Themechanismsbywhichperoxynitriteexertsitsprotectiveeffectmayincludeimprovementofpost-ischaemiccerebrovascularfunction,leadingtoenhancementofblood owtotheischaemicterritory,andexpressionofprosurvivalgenesresultingincytoprotection.TheevidencesuggeststhatNOcanengagehighlyeffectiveandmultifunctionalprosurvivalpathways,whichcouldbeexploitedforthepreventionandtreatmentofcerebrovascularpathologies.

(Received18April2011;acceptedafterrevision9July2011; rstpublishedonline11July2011)

CorrespondingauthorC.Iadecola:DivisionofNeurobiology,407East61stStreet,Room304,NewYork,NY10065,USA.Email:coi2001@med.cornell.edu

AbbreviationsAG,aminoguanidine;BDNF,brainderivedneurotrophicfactor;CBF,cerebralblood ow;COX-2,cyclooxygenase-2;CREB,cyclicadenosinemonophosphateresponseelementbinding;eNOS,endothelialnitricoxidesynthase;ERK,extracellular-signal-regulatedkinase;FeTTPS,5,10,15,20-tetrakis(4-sulfonatophenyl)prophyrinatoiron(III);HDAC2,histonedeacetylase2;iNOS,induciblenitricoxidesynthase;KEAP1,kelch-likeECH-associatedprotein1;LPS,lipopolysaccharide;NADPH,nicotinamideadeninedinucleotidephosphate;nNOS,neuronalnitricoxidesynthase;NO,nitricoxide;Nox2,NADPHoxidase2;Nrf2,nuclearfactorerythroid2-relatedfactor2;PKG,proteinkinaseG;sGC,solubleguanylyl

cyclase.

CostantinoIadecola,MD,istheG.C.CotziasDistinguishedProfessorofNeurologyandNeuroscienceandChiefoftheDivisionofNeurobiologyatWeillCornellMedicalCollege,NewYorkCity.Hisresearchfocusesonneurovascularregulation,themolecularpathologyofischaemia,andontheinterfacebetweenstrokeandAlzheimer’sdisease.Hehaspublishedover200papers.HehasservedontheResearchCommitteeoftheAHAandontheStrokeCouncil.HehaschairedtheInternationalStrokeConference,isPresident(Chair)oftheScienti cAdvisoryCommitteeoftheFondationLeducqandanadvisortotheCanadian,EuropeanandGermanStrokeNetworks.HeisconsultingeditorforStroke,reviewingeditorforTheJournalofNeuroscience,andguesteditorforPNASandCirculation.HeisontheeditorialboardoftheAnnalsofNeurology,theAmericanJournalofPhysiology(HeartCircPhysiol),CerebrovascularDiseases,andtheJournalofCerebralBloodFlowandMetabolism.HehasreceivedtheLaurenceMcHenryAward(AAN),theLouisSklarowMemorialAward,theEstablishedInvestigatorAward(AHA),andtheJacobJavitsAward(NINDS).In2009,hereceivedtheWillisAward,thehighesthonourbestowedbytheAHAinstrokeresearch.

ThisreportwaspresentedatTheJournalofPhysiologySymposiumonMolecularmechanismsunderlyingneurovascularprotectioninstroke,whichtookplaceatExperimentalBiology2011,Washington,DC,USAon10April2011.ItwascommissionedbytheEditorialBoardandre ectstheviewsoftheauthors.

C2011TheAuthors.Journalcompilation C2011ThePhysiologicalSociety

DOI:10.1113/jphysiol.2011.210831

4138C.Iadecolaandothers

JPhysiol589.17

Introduction

Organismsfacevariousdestructivethreats,suchasinfection,ischaemiaortrauma,and,consequently,havedevelopedmechanismsforself-protectionfromtissuedamage.Inthiscontext,theterm‘preconditioning’describesaprocessbywhichapotentiallyharmfulstimulusamelioratestissuedamagewhenappliedinasub-lethalfashionbeforetheinjury.Forexample,shortperiodsofnon-lethalcerebralischaemiareducethebraindamageproducedbyasubsequentlethalischaemicinsult(Gidday,2006).Thisphenomenon,calledischaemictolerance,was rstreportedinvivoin1964(Dahl&Balfour,1964)andis ttinglydescribedbythequoteoftheGermanphilosopherFriedrichNietzsche:‘Whatdoesnotdestroymemakesmestronger’(Nietzsche,2007).

Preconditioningcanbeinducedbyawidevarietyofstimuli,includinghypoxia-ischaemia,anaesthetics,hyperthermia,corticalspreadingdepressions,mitochondrialtoxins,orproin ammatoryagents,suchaslipopolysaccharide(LPS)(Gidday,2006).Tolerancecandevelopminutestohoursafterthepreconditioningstimulus(earlypreconditioning).Earlypreconditioningdoesnotrequireproteinsynthesisanddependsonsignallingpathwaysactivatedbythepreconditioningstimulus(Staglianoetal.1999;Orioetal.2007).Alonger-lastingtypeoftolerance(delayedorlatepre-conditioning)occursdaysaftertheinducingstimulusandcanlastforweeks(Reisetal.1998;Gidday,2006;Stoweetal.2011).Delayedpreconditioningrequiresdenovoproteinsynthesis(Kitagawaetal.1990).Themechanismsofpreconditioninghavebeenstudiedextensivelyandhavebeenrecentlyreviewed(Perez-Pinzonetal.2005;Gidday,2006;Stenzel-Pooreetal.2007;Dirnagletal.2009).Theevidencesuggeststhatpreconditioningismediatedbymultiplepathwaysthatactinconcerttoprotectthebrainbyreducingenergyexpenditures,improvingthedeliveryofblood ow,suppressingthepathogenicpathwaystriggeredbycerebralischaemia,andmaximizingtherepairpotentialofthedamagedtissue(Dirnagletal.2009).Inthecontextofdelayedpreconditioning,theseeffectsareassociatedwith,andperhapsdrivenby,aprofoundreprogrammingofpost-ischaemicgeneexpression(Stenzel-Pooreetal.2003).

Amongthemanyfactorsinvolvedinthecomplexchainofeventsleadingtoischaemicpreconditioning,nitricoxide(NO),apleiotr …… 此处隐藏：36706字，全部文档内容请下载后查看。喜欢就下载吧 ……