Augmented Atherogenesis in LDL Receptor Deficient Mice Lacking Both Macrophage ABCA1 and ApoE 英文参考文献.docVIP
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Augmented Atherogenesis in LDL Receptor Deficient Mice Lacking Both Macrophage ABCA1 and ApoE 英文参考文献
AugmentedAtherogenesisinLDLReceptorDeficient
MiceLackingBothMacrophageABCA1andApoE
BartLammers*,YingZhao,MennoHoekstra,ReeniB.Hildebrand,DanYe,IllianaMeurs,TheoJ.C.Van
Berkel,MirandaVanEck
DivisionofBiopharmaceutics,Leiden/AmsterdamCenterforDrugResearch,GorlaeusLaboratories,LeidenUniversity,Leiden,TheNetherlands
Abstract
Aim:ABCA1protectsagainstatherosclerosisbyfacilitatingcholesteroleffluxfrommacrophagefoamcellsinthearterialwall
toextracellularapolipoprotein(apo)A-I.IncontrasttoapoA-I,apoEissecretedbymacrophagesandcan,likeapoA-I,induce
ABCA1-mediated cholesterol efflux.Yet, thecombined effect ofmacrophage ABCA1 and apoEon lesion development is
unexplored.
MethodsandResults:LDLreceptorknockout(KO)miceweretransplantedwithbonemarrowfromABCA1/apoEdoubleKO
(dKO)mice,theirrespectivesingleKO’s,andwild-type(WT)controlsandwerechallengedwithahigh-fat/high-cholesterol
dietfor9weeks.InvitrocholesteroleffluxexperimentsshowednodifferencesbetweenABCA1KOanddKOmacrophages.
Theserumnon-HDL/HDLratioindKOtransplantedmicewas1.7-foldand2.4-fold(p,0.01)increasedcomparedtoWTand
ABCA1KOtransplantedmice,respectively.TheatheroscleroticlesionareaindKOtransplantedanimals(6506946103 mm2),
however, was 1.9-fold (p,0.01) and 1.6-fold (p,0.01) increased compared to single knockouts (ABCA1 KO:
3416206103 mm2; apoE KO: 4026786103 mm2, respectively) and 3.1-fold increased (p,0.001) compared to WT
(2116206103 mm2). When normalized for serum cholesterol exposure, macrophage ABCA1 and apoE independently
protectedagainstatheroscleroticlesiondevelopment(p,0.001).Moreover,hepaticexpressionlevelsofTNFaandIL-6were
highlyinducedindKOtransplantedanimals(3.0-fold;p,0.05,and4.3-fold;p,0.001,respectively).Inagreement,serumIL-6
levelswerealsoenhancedinABCA1KOtransplantedmice(p,0.05)andevenfurtherenhancedindKOtransplantedanimals
(3.1-foldascomparedtoABCA1KOtransplantedanimals;p,0.05).
Conclusions:CombineddeletionofmacrophageABCA1andapoEresultsinadefectincholesteroleffluxand,comparedto
ABCA1KOtransplant
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