【高血压英文课件】-cardiovascular-disease-(CVD)

CVDHalfofallAmericansdiefromcardiovasculardisease(CVD)Ischemic(Coronary)HeartDiseaseHypertensiveDiseaseRheumaticFever/RheumaticHeartDiseaseCerebrovascularDisease(Stroke)Estimated2001CVDcost=$300billion($180billionindirecthealthcarecosts)3/4ofallCVDdeathsaretheresultofatherosclerosis.CVDHalfofallAmericansdiefIntima-endothelialcellsandtheinternalelasticlaminaMedia-consistsofsmoothmusclecellsandmoreelasticlayersAdventitia-consistsofconnectivetissue,fatcells,nervesandotherstuffIntima-endothelialcellsandDefinitionAtherosclerosis:Adiseaseoflargeandmedium-sizedarteriesthatresultsinprogressiveaccumulationofsmoothmusclecellsandlipidswithintheintima.TypicallykillsbyinducingmyocardialinfarctionDifferentfromarteriosclerosis(hardeningofthearteries),whichisduetocalcificationofthearterialwall.DefinitionAtherosclerosis:Ad【高血压英文课件】-cardiovascular-disease-(CVD)【高血压英文课件】-cardiovascular-disease-(CVD)LDLLDLOxidizedLDLInducesleukocyte“homing”EndotheliumVesselLumenMonocyteOxidizedLDLMacrophageAdhesion

MoleculesCytokinesIntimaLDLLDLOxidizedLDLInducesleuLDLLDLEndotheliumVesselLumenMonocyteMacrophageAdhesion

MoleculesMacrophagestakeupmodifiedLDLFoamCellOxidizedLDLTakenupbyMacrophageIntimaNecrosisfreesthemodifiedLDLLDLLDLEndotheliumVesselLumenMFoamcellsandmacrophagesFoamcellsandmacrophagesEtiologyWhatisthe"trigger"forinitiationofthedisease?HemodynamicstressBacterialinfection,particularlyperiodontaldiseaseHighlipidcocentrationsEtiologyWhatisthe"trigger"EtiologyFattystreaksaretypicallyfoundinteenagers,sothediseasebeginsearly.Occurrenceincreaseswithobesitydiabeteshighlipid/cholesteroldietsincreasingagehighbloodpressureGeneticfactorsareprevalent(likeinfamilialhypercholesterolemia)EtiologyFattystreaksaretypiFamilialHypercholesterolemiaIncidence:1in500ThemostcommonknownformofgeneticdiseaseResultsin2Xto6XincreaseinserumcholesterolSevereandearlyatherosclerosisandmyocardialinfarctionDiagnosedontheabovetwoitems,andafamilyhistoryEtiologyMutationsinthegenecodingforLDLreceptorsFamilialHypercholesterolemiaI【高血压英文课件】-cardiovascular-disease-(CVD)Proteinsynthesis,expostandimportProteinsynthesis,expostandWaystogetproteinsintoorganellesormembranesCo-translationalimportPutproteinsintoorganellesormembranesduringtheactualprocessoftranslationExamples:extracellularproteins,cellmembranes,lysosomalenzymesPost-translationalimportMakeproteinsinthecytoplasm,andsubsequentlyimportthemintotheorganelleofchoiceExamples:thenucleus,themitochondrionEachisdirectedby“signals”embeddedintheaminoacidsequenceofthenewlysynthesizedproteinWaystogetproteinsintoorgaCo-translationalimportofproteinsCo-translationalimportofpro【高血压英文课件】-cardiovascular-disease-(CVD)Stop-transferor“topogenic”sequencesSequencesof20hydrophobicaminoacidsbindinsidetheporeMovelaterallyoutoftheporeandintothemembranetobuildatransmembraneprotein.TherecanbemultipletopogenicsequencesinasinglepolypeptidechainStop-transferor“topogenic”sProteintraffickingIntheabsenceofanysignalortargetingsequence,proteinsaremadeandremaininthecytoplasmCo-translationalimportThedefaultdestinationisexportfromthecellortothecellmembraneTargetingsequencescandirectthemelsewherePost-translationalimportNuclearlocalizationsequences(NLS)targetproteinsforimportintothenucleusaftertranslation.TransitsequencessimilarlytargetproteinsforimportintothemitochondrionProteintraffickingIntheabsePost-translationalimportintothenucleusNuclearproteinscontainanuclearlocalizationsignal(NLS)Theseproteinsaremadebyfree

ribosomes(notER-bound)ImportinbindstotheNLSThenuclearpore

recognizesand

transports

importin

andthe

proteinPost-translationalimportintoPost-translationalmodificaticationsintheRERNewlysynthesizedpolypeptidesinthemembraneandlumenoftheERundergofiveprincipalmodificationsFormationofdisulfidebondsProperfoldingSpecificproteolyticcleavagesAssemblyintomultimericproteinsAdditionandprocessingofcarbohydrates(glycosylation)Post-translationalmodificaticN-andO-linkedoligosaccharidesOligosaccharidesOligo:fewO-linkedSugarslinkedtohydroxyloxygenonserineorthreonineTendtobeshort

N-linkedSugarslinkedtoamidenitrogenonasparagineTendtobelongandhighlybranchedN-andO-linkedoligosaccharidABObloodtypeisdeterminedbytwoglycosyltransferasesABObloodtypeisdeterminedbEndocytosis,andmembranecyclingEndocytosis,andmembranecyclHowavesicleforms:theclathrin-coatedpitHowavesicleforms:theclathStructureofaclathrin-coatedvesicleClathrinFormstriskelionsConsistsofthreeheavychainsandthreelightchains.Coatsalsocontainadaptorproteinsthatlinkmembranereceptorstotheclathrincoat.Assemblycausesthebuddingofacoatedvesicle,completelyenclosedbyclathrinThisisoftencalled“receptor-mediatedendocytosis”Structureofaclathrin-coated【高血压英文课件】-cardiovascular-disease-(CVD)ThreetypesofcoatedvesiclesClathrinCellmembraneandGolgitoendosomesCoatomersCOPIRetrogradethroughgolgistackGolgitoRoughERCOPIIRoughERtoGolgiThreetypesofcoatedvesiclesProteintargeting:lysozomalenzymesLysosomal

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

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

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

tomakehypochlorousacid

(HOCl).HOClisdeadlytobacteria.MyeloperoxidaseisgreenROSaremadedeliberatelybywHowyoumitigatetheireffectsO2·O2-H2O22H2O+O2EnzymescavengersGlutathione(GSH),an“antioxidant”SuperoxidedismutaseSODCatalase2GSSG+2H2O2GSHGSHPeroxidaseHowyoumitigatetheireffects·OHno!TheFentonreactionGeneratesahydroxylradicalthroughtheoxidationofferrousironbyperoxideTheHaber-WeissreactionGeneratesahydroxylradicalthroughareactionofsuperoxidewithperoxide·OHno!TheFentonreaction·OH?Sowhat?AfreeradicalchainreactioncanbeinitiatedInthisdiagram,Lrepresentsafattyacidchain(lipid)Howdoyou

stopit?·OHH2OLHL·LOO·LHLOOHLO·O2Fe2+·OH?Sowhat?AfreeradicalchAntioxidantsfoundinLDLα-tocopherolandγ-tocopherolFormsofvitaminEhighestconcentrationofantioxidantsinLDLdepletedfirstβ-caroteneAcarotenoidprecursorofvitaminAabundantinbrightlycoloredfruitsandvegetablesOthercarotenoidsα-caroteneLycopene (redpigmentinvegetables)Crptoxanthin/CantaxanthinLuteinUbiquinolTheonlyfat-solubleantioxidantyourcellsmakeAntioxidantsfoundinLDLα-tocTreatmentsforFHCLowfatdiet,nosmoking,etc…DrugtreatmentDietaryion-exchangeresinstobindbileacids,andhelpspreventcholesterolabsorptionintheintestineNicotinicacid(niacin,B3),whichenhancesLDLuptakeEstrogenreplacementinpost-menopausalwomen

CholesterolsynthesisinhibitorsLivertransplantThelivercontains70%ofthebody’sLDLreceptorsTreatmentsforFHCLowfatdietCVDHalfofallAmericansdiefromcardiovasculardisease(CVD)Ischemic(Coronary)HeartDiseaseHypertensiveDiseaseRheumaticFever/RheumaticHeartDiseaseCerebrovascularDisease(Stroke)Estimated2001CVDcost=$300billion($180billionindirecthealthcarecosts)3/4ofallCVDdeathsaretheresultofatherosclerosis.CVDHalfofallAmericansdiefIntima-endothelialcellsandtheinternalelasticlaminaMedia-consistsofsmoothmusclecellsandmoreelasticlayersAdventitia-consistsofconnectivetissue,fatcells,nervesandotherstuffIntima-endothelialcellsandDefinitionAtherosclerosis:Adiseaseoflargeandmedium-sizedarteriesthatresultsinprogressiveaccumulationofsmoothmusclecellsandlipidswithintheintima.TypicallykillsbyinducingmyocardialinfarctionDifferentfromarteriosclerosis(hardeningofthearteries),whichisduetocalcificationofthearterialwall.DefinitionAtherosclerosis:Ad【高血压英文课件】-cardiovascular-disease-(CVD)【高血压英文课件】-cardiovascular-disease-(CVD)LDLLDLOxidizedLDLInducesleukocyte“homing”EndotheliumVesselLumenMonocyteOxidizedLDLMacrophageAdhesion

MoleculesCytokinesIntimaLDLLDLOxidizedLDLInducesleuLDLLDLEndotheliumVesselLumenMonocyteMacrophageAdhesion

MoleculesMacrophagestakeupmodifiedLDLFoamCellOxidizedLDLTakenupbyMacrophageIntimaNecrosisfreesthemodifiedLDLLDLLDLEndotheliumVesselLumenMFoamcellsandmacrophagesFoamcellsandmacrophagesEtiologyWhatisthe"trigger"forinitiationofthedisease?HemodynamicstressBacterialinfection,particularlyperiodontaldiseaseHighlipidcocentrationsEtiologyWhatisthe"trigger"EtiologyFattystreaksaretypicallyfoundinteenagers,sothediseasebeginsearly.Occurrenceincreaseswithobesitydiabeteshighlipid/cholesteroldietsincreasingagehighbloodpressureGeneticfactorsareprevalent(likeinfamilialhypercholesterolemia)EtiologyFattystreaksaretypiFamilialHypercholesterolemiaIncidence:1in500ThemostcommonknownformofgeneticdiseaseResultsin2Xto6XincreaseinserumcholesterolSevereandearlyatherosclerosisandmyocardialinfarctionDiagnosedontheabovetwoitems,andafamilyhistoryEtiologyMutationsinthegenecodingforLDLreceptorsFamilialHypercholesterolemiaI【高血压英文课件】-cardiovascular-disease-(CVD)Proteinsynthesis,expostandimportProteinsynthesis,expostandWaystogetproteinsintoorganellesormembranesCo-translationalimportPutproteinsintoorganellesormembranesduringtheactualprocessoftranslationExamples:extracellularproteins,cellmembranes,lysosomalenzymesPost-translationalimportMakeproteinsinthecytoplasm,andsubsequentlyimportthemintotheorganelleofchoiceExamples:thenucleus,themitochondrionEachisdirectedby“signals”embeddedintheaminoacidsequenceofthenewlysynthesizedproteinWaystogetproteinsintoorgaCo-translationalimportofproteinsCo-translationalimportofpro【高血压英文课件】-cardiovascular-disease-(CVD)Stop-transferor“topogenic”sequencesSequencesof20hydrophobicaminoacidsbindinsidetheporeMovelaterallyoutoftheporeandintothemembranetobuildatransmembraneprotein.TherecanbemultipletopogenicsequencesinasinglepolypeptidechainStop-transferor“topogenic”sProteintraffickingIntheabsenceofanysignalortargetingsequence,proteinsaremadeandremaininthecytoplasmCo-translationalimportThedefaultdestinationisexportfromthecellortothecellmembraneTargetingsequencescandirectthemelsewherePost-translationalimportNuclearlocalizationsequences(NLS)targetproteinsforimportintothenucleusaftertranslation.TransitsequencessimilarlytargetproteinsforimportintothemitochondrionProteintraffickingIntheabsePost-translationalimportintothenucleusNuclearproteinscontainanuclearlocalizationsignal(NLS)Theseproteinsaremadebyfree

ribosomes(notER-bound)ImportinbindstotheNLSThenuclearpore

recognizesand

transports

importin

andthe

proteinPost-translationalimportintoPost-translationalmodificaticationsintheRERNewlysynthesizedpolypeptidesinthemembraneandlumenoftheERundergofiveprincipalmodificationsFormationofdisulfidebondsProperfoldingSpecificproteolyticcleavagesAssemblyintomultimericproteinsAdditionandprocessingofcarbohydrates(glycosylation)Post-translationalmodificaticN-andO-linkedoligosaccharidesOligosaccharidesOligo:fewO-linkedSugarslinkedtohydroxyloxygenonserineorthreonineTendtobeshort

N-linkedSugarslinkedtoamidenitrogenonasparagineTendtobelongandhighlybranchedN-andO-linkedoligosaccharidABObloodtypeisdeterminedbytwoglycosyltransferasesABObloodtypeisdeterminedbEndocytosis,andmembranecyclingEndocytosis,andmembranecyclHowavesicleforms:theclathrin-coatedpitHowavesicleforms:theclathStructureofaclathrin-coatedvesicleClathrinFormstriskelionsConsistsofthreeheavychainsandthreelightchains.Coatsalsocontainadaptorproteinsthatlinkmembranereceptorstotheclathrincoat.Assemblycausesthebuddingofacoatedvesicle,completelyenclosedbyclathrinThisisoftencalled“receptor-mediatedendocytosis”Structureofaclathrin-coated【高血压英文课件】-cardiovascular-disease-(CVD)ThreetypesofcoatedvesiclesClathrinCellmembraneandGolgitoendosomesCoatomersCOPIRetrogradethroughgolgistackGolgitoRoughERCOPIIRoughERtoGolgiThreetypesofcoatedvesiclesProteintargeting:lysozomalenzymesLysosomal

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

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

when,andwhyofreactiveoxygenspecies(ROS)Bynumerouscells,duringmanydiseaseprocesses,asanunfortunatecauseorside-effectInalmostallcells,allthetime,forcellsignalingBywhitebloodcells,duringinflammation,tofightinfectionIn