【高血壓英文課件】-cardiovascular-disease-(CVD)

CVDHalfofallAmericansdiefromcardiovasculardisease(CVD)Ischemic(Coronary)HeartDiseaseHypertensiveDiseaseRheumaticFever/RheumaticHeartDiseaseCerebrovascularDisease(Stroke)Estimated2001CVDcost=$300billion($180billionindirecthealthcarecosts)3/4ofallCVDdeathsaretheresultofatherosclerosis.Intima-endothelialcellsandtheinternalelasticlaminaMedia-consistsofsmoothmusclecellsandmoreelasticlayersAdventitia-consistsofconnectivetissue,fatcells,nervesandotherstuffDefinitionAtherosclerosis:Adiseaseoflargeandmedium-sizedarteriesthatresultsinprogressiveaccumulationofsmoothmusclecellsandlipidswithintheintima.TypicallykillsbyinducingmyocardialinfarctionDifferentfromarteriosclerosis(hardeningofthearteries),whichisduetocalcificationofthearterialwall.LDLLDLOxidizedLDLInducesleukocyte“homing”EndotheliumVesselLumenMonocyteOxidizedLDLMacrophageAdhesion

MoleculesCytokinesIntimaLDLLDLEndotheliumVesselLumenMonocyteMacrophageAdhesion

MoleculesMacrophagestakeupmodifiedLDLFoamCellOxidizedLDLTakenupbyMacrophageIntimaNecrosisfreesthemodifiedLDLFoamcellsandmacrophagesEtiologyWhatisthe"trigger"forinitiationofthedisease?HemodynamicstressBacterialinfection,particularlyperiodontaldiseaseHighlipidcocentrationsEtiologyFattystreaksaretypicallyfoundinteenagers,sothediseasebeginsearly.Occurrenceincreaseswithobesitydiabeteshighlipid/cholesteroldietsincreasingagehighbloodpressureGeneticfactorsareprevalent(likeinfamilialhypercholesterolemia)FamilialHypercholesterolemiaIncidence:1in500ThemostcommonknownformofgeneticdiseaseResultsin2Xto6XincreaseinserumcholesterolSevereandearlyatherosclerosisandmyocardialinfarctionDiagnosedontheabovetwoitems,andafamilyhistoryEtiologyMutationsinthegenecodingforLDLreceptorsProteinsynthesis,expostandimportWaystogetproteinsintoorganellesormembranesCo-translationalimportPutproteinsintoorganellesormembranesduringtheactualprocessoftranslationExamples:extracellularproteins,cellmembranes,lysosomalenzymesPost-translationalimportMakeproteinsinthecytoplasm,andsubsequentlyimportthemintotheorganelleofchoiceExamples:thenucleus,themitochondrionEachisdirectedby“signals”embeddedintheaminoacidsequenceofthenewlysynthesizedproteinCo-translationalimportofproteinsStop-transferor“topogenic”sequencesSequencesof20hydrophobicaminoacidsbindinsidetheporeMovelaterallyoutoftheporeandintothemembranetobuildatransmembraneprotein.TherecanbemultipletopogenicsequencesinasinglepolypeptidechainProteintraffickingIntheabsenceofanysignalortargetingsequence,proteinsaremadeandremaininthecytoplasmCo-translationalimportThedefaultdestinationisexportfromthecellortothecellmembraneTargetingsequencescandirectthemelsewherePost-translationalimportNuclearlocalizationsequences(NLS)targetproteinsforimportintothenucleusaftertranslation.TransitsequencessimilarlytargetproteinsforimportintothemitochondrionPost-translationalimportintothenucleusNuclearproteinscontainanuclearlocalizationsignal(NLS)Theseproteinsaremadebyfree

ribosomes(notER-bound)ImportinbindstotheNLSThenuclearpore

recognizesand

transports

importin

andthe

proteinPost-translationalmodificaticationsintheRERNewlysynthesizedpolypeptidesinthemembraneandlumenoftheERundergofiveprincipalmodificationsFormationofdisulfidebondsProperfoldingSpecificproteolyticcleavagesAssemblyintomultimericproteinsAdditionandprocessingofcarbohydrates(glycosylation)N-andO-linkedoligosaccharidesOligosaccharidesOligo:fewO-linkedSugarslinkedtohydroxyloxygenonserineorthreonineTendtobeshort

N-linkedSugarslinkedtoamidenitrogenonasparagineTendtobelongandhighlybranchedABObloodtypeisdeterminedbytwoglycosyltransferasesEndocytosis,andmembranecyclingHowavesicleforms:theclathrin-coatedpitStructureofaclathrin-coatedvesicleClathrinFormstriskelionsConsistsofthreeheavychainsandthreelightchains.Coatsalsocontainadaptorproteinsthatlinkmembranereceptorstotheclathrincoat.Assemblycausesthebuddingofacoatedvesicle,completelyenclosedbyclathrinThisisoftencalled“receptor-mediatedendocytosis”ThreetypesofcoatedvesiclesClathrinCellmembraneandGolgitoendosomesCoatomersCOPIRetrogradethroughgolgistackGolgitoRoughERCOPIIRoughERtoGolgiProteintargeting:lysozomalenzymesLysosomal

hydrolasesaretaggedwithmannose-6-phosphate.Theenzymethatdoesthisrecognizesasignalpatchonthefoldedhydrolase.Mannose-6phosphatebindstoaM6Preceptorthatconcentratesitintoa"coatedpit"LipoproteinsConsistofCholesterolesterswithfattyacids,ortriacylglycerols…surroundedbyaphospholipidmonolayer…containingcholesterol…andoneormore

apoprotein“handles”Intestine:chylomicronsform.Thesearespheresofcholesterolandtriglyceridessurroundedbyphospholipidandapoproteins,forwhichvarioustissueshavereceptors.Theliverformsverylowdensitylipoproteins(VLDL)fortransportoftriglyceridestoadiposetissueandmuscleOncethetriglyceridesaretakenup,anapoproteinmaybelostresultinginlowdensitylipoprotein(LDL)withasingleapoproteinb(Apo-B).LDLsarenottakenupquickly,butresideinthebloodforextendedperiods.Theynormallydelivercholesteroltoperipheraltissues.Theliversecreteshighdensitylipoproteins(HDL)whicharelowincholesterol.Thesetakeupcholesterolfromperipheraltissues,andreturnittotheliver.Q&AQ:Doyouneedcholesterolforanything?A:Yes…forsteroidhormonesandmembranesQ:Canyoumakeyourowncholesterol?A:Yes,youcan.Primarilyintheliver,inthesmoothendoplasmicreticulum.Q:Howdoesyourbodyregulatetheamountofcholesterolthatismade?feedbackcontrolofcholesterolsynthesisFamilialHypercholesterolemiaMutationsintheLDLreceptormaycauseFailuretoexpressreceptors,orPoorapoproteinBbinding,andthereforePoorinternalizationthroughreceptormediatedendocytosisNointernalizationnofeedbacktopreventcholesterolsynthesisNofeedbackexcesssynthesisofcholesterolExcesscholesterolRapidlipidaccumulationButhowdotheybecomeoxidized?Thewhere,

when,andwhyofreactiveoxygenspecies(ROS)Bynumerouscells,duringmanydiseaseprocesses,asanunfortunatecauseorside-effectInalmostallcells,allthetime,forcellsignalingBywhitebloodcells,duringinflammation,tofightinfectionInmitochondria,allthetime,asanormalbyproductSuperoxide(·O2-)andperoxide(O2-2)inrespirationROSaremadedeliberatelybywhitecellsA“respiratoryburst”generatinglargequantitiesof·O2-(superoxide)·O2-isantibacterialNADPHoxidaseNeutrophilsuseH2O2andCl-

tomakehypochlorousacid

(HOCl).HOClisdeadlytobacteria.MyeloperoxidaseisgreenHowyoumitigatetheireffectsO2·O2-H2O22H2O+O2EnzymescavengersGlutathione(GSH),an“antioxidant”SuperoxidedismutaseSODCatalase2GSSG+2H2O2GSHGSHPeroxidase·OHno!TheFentonreactionGeneratesahydroxylradicalthroughtheoxidationofferrousironbyperoxideTheHaber-WeissreactionGeneratesahydroxylradicalthroughareactionofsuperoxidewithperoxide·OH?Sowhat?AfreeradicalchainreactioncanbeinitiatedInthisdiagram,Lrepresentsa