LDL信号通路总结

Atherosclerosis,achronicinflammatorydiseaseofthearterialwall,isthemajorcauseofmorbidityandmortalityfromCVD(CardiovascularDisease)inmuchoftheworld’spopulation.ThediseaseinvolvestheformationofPlaquesinarterialwallsthatnarrowthearterialpassage,restrictingbloodflowandincreasingtheriskofocclusionofbloodflowbyamyocardialinfarction.ThereisnowaconsensusthatAtherosclerosisrepresentsastateofheightenedoxidativestresscharacterizedbylipidandproteinoxidationinthevascularwall.TheOxidativeModificationhypothesispredictsLDL(Low-DensityLipoproteins)oxidationasanearlyeventinAtherosclerosis,andoxidizedLDLasoneoftheimportantcontributorsofAtherogenesis(Ref.1,2&3).Lipoproteinsarewater-solublesphericalparticlesthattransportnonpolarlipids.Inhumans,LDLsarethemajorCholesteroltransportersandconsistofahydrophobiccorecontainingCholesterylestermolecules,Triacylglycerols;andasurfacemonolayerofpolarlipids(primarilyPhospholipids)andApoB(Apolipoprotein-B)(Ref.4).LDLiscommonlyreferredtoas“BadCholesterol”duetoitsroleinpromotingAtherosclerosis.OxidationofLDLintheArterywallisoneofthemajorphysiologicallyrelevantmechanismsforthepathogenesisofAtherosclerosis(Ref.5).LDLintheplasmaoriginatesfromvLDL(very-LowDensityLipoprotein)producedbytheliver.vLDLisconvertedtoLDLbytheactionofLPL(LipoproteinLipase),anenzymethathydrolyzestriglyceridesinvLDL,removingthemfromthevLDLparticleandreleasingfreefattyacids.TheremovaloftriglyceridesfromvLDLbyLPLleavesagreaterproportionofCholesterol,increasingthedensityoftheparticleandchangingittoLDL.OneofthefirststepsinthedevelopmentofAtherosclerosisisthepassageofLDLoutoftheArteriallumenintotheArterialwall.PlasmaLDListransportedacrosstheintactEndotheliumandbecomestrappedintheECM(ExtracellularMatrix)ofthesubendothelialspacewhereitissubjectedtooxidativemodificationstoproducehighlyoxidizedandaggregatedLDL,referredtoasOxLDL(OxidizedLDL).OxLDLsarebelievedtobethemostAtherogenicformsofLDL.Variouscellularandbiochemicalmediators:ROS(ReactiveOxygenSpecies),theenzymesSMase(Sphingomyelinase),sPLA2(SecretoryPhospholipase-2),otherLipases,andMPO(Myeloperoxidase),havebeenproposedtoinitiateandregulateLDLoxidationandaggregation.ThevariouscomponentsinOxLDLincludeLipidHydroperoxides,Oxysterols,Lysophosphatidylcholine,andAldehydes(Ref.6).OxLDLisapotentinducerofinflammatorymolecules.ItstimulatesinflammatorysignalingbyEndothelialcells,releasingchemotacticproteinssuchasMCP1(MonocyteChemotacticProtein-1)andgrowthfactorssuchasmCSF(MonocyteColonyStimulatingFactor),whichhelpintherecruitmentofMonocytesintotheArterialwall(Ref.4).OxLDLsalsopromotethedifferentiationofMonocytesintoMacrophagesthattake-uptheoxidizedLDLinaprocessthatconvertsthemintoFoamcells,thehallmarkcellofAtherosclerosis.Apartfromthat,OxLDLalsohasothereffects,suchasinhibitingtheproductionofNO(NitricOxide),animportantmediatorofvasodilationandexpressionofendothelialleukocyteadhesionmolecules.TheoxLDLparticlesarerecognizedbyMacrophageScavengerReceptors:SR-A(ScavengerReceptor-A),CD36(CD36Antigen)andCD68(MacrophageAntigenCD68).TheMacrophagestakeuptheOxLDLs,becomeenlargedandfulloflipid.Thesecellsaccumulateintissueandaretransformedintolipid-ladenFoamcells,dyingandformingpartoftheAtherogenicPlaque(AtheroscleroticPlaque)inthefattystreaklesions(Ref.5).ActivatedMacrophagesexpressarangeofcytokines(suchasTNF-Alpha(TumorNecrosisFactor-Alpha),IL-1Beta(Interleukin-1Beta),MIP1Alpha(MacrophageInflammatoryProtein-1Alpha)etc.),whichstimulateendothelialcellstoexpressadhesionproteins(likeVCAM1(Vascular-Cell-AdhesionMolecule-1),ICAM1(Intracellular-AdhesionMolecule-1)etc).ThisfacilitatestheprocessofbindingofadditionalbloodMonocytestotheEndotheliumandtheirrecruitmentintotheIntima.ThecytokinesreleasedfromtheMacrophagesandFoamcellsalsostimulatetheSMCstomigrateintotheIntima,thenproliferateandsecreteCollagen,ElastinandProteoglycanstoformafibrousmatrix.ThisresultsintheformationofPlaqueswithfibrouscaps(Ref.7).ThematureAtheroscleroticPlaqueconsistsofafibrouscap—comprisingvariablenumbersofSMCs,foamyMacrophages,Lymphocytes,Extracellular-MatrixandavarietyofInflammatoryMediators—whichencapsulatesanacellular,lipid-richnecroticcorethatisderived,inpart,fromdeadFoamcells.ThematurePlaquesprotrudeintotheArteriallumen,andcauseobstructionofArterialbloodflow.Althoughadvancedlesionscanimpedebloodflow,MyocardialInfarctionsandstrokesresultfromanacuteocclusionthatisduetotheformationofaThrombus,whichformsinresponsetoruptureorerosionofthePlaques.AmongvariousfactorsthatmaydestabilizePlaquesandpromoteThrombosisareinfection,whichmayhavesystemiceffectssuchasinductionofAcutePhaseProteinsandlocaleffectssuchasincreasedexpressionofTF(TissueFactor)anddecreasedexpressionofPA(PlasminogenActivator).Numerousphysiologictriggers:Physicalexertion,mechanicalstressduetoanincreaseinCardiaccontractility,PulseRate,BloodPressureandpossibly,VasoconstrictioninitiatetheruptureofavulnerablePlaque.Ruptureleadstotheactivation,adhesion,andaggregationofPlateletsandtheactivationoftheClottingCascade,resultingintheformationofanocclusiveThrombus(Clot).Thrombusformationinthelum