苹果多份能减轻动脉粥样硬化和脂肪肝

Nutrients2015,7,7085-7105;doi:10.3390/nu7085324OPENACCESSnutrientsISSN2072-6643
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MicethroughtheROS/MAPK/NF-BPathwayZhe-RongXu1,:,Jin-YouLi1,:,Xin-WeiDong2,Zhong-JuTan1,Wei-ZhenWu1,Qiang-MinXie2,3,*andYun-MeiYang1,*1DepartmentofGeriatrics,FirstAffiliatedHospital,SchoolofMedicine,ZhejiangUniversity,Hangzhou310003,China;E-Mails:[e-mail](Z.-R.X.);[e-mail](J.-Y.L.);[e-mail](Z.-J.T.);[e-mail](W.-Z.W.)2DepartmentofPharmacology,SchoolofMedicine,ZhejiangUniversity,Hangzhou310058,China;E-Mail:[e-mail]3AnimalLaboratoyCenterofZhejiangUniversity,Hangzhou310058,China:Theseauthorscontributedequallytothiswork.*Authorstowhomcorrespondenceshouldbeaddressed;E-Mails:[e-mail](Q.-M.X.);[e-mail](Y.-M.Y.);Tel.:[phone](Q.-M.X.);[phone](Y.-M.Y.);Fax:[phone](Q.-M.X.);[phone](Y.-M.Y.).Received:16July2015/Accepted:13August2015/Published:24August2015Abstract:Inthisstudy,weexaminedtheeffectsofapplepolyphenols(APs)onhyperlipidemia,atherosclerosis,hepaticsteatosisandendothelialfunctionandinvestigatedthepotentialmechanisms.ApoE
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micewerefedawestern-typedietandorallytreatedwithAPs(100mg/kg)oratorvastatin(10mg/kg)for12weeks.Hyperlipidemiaandatherosclerosisintheaorticsinusesand,andhepaticlipidosisweremeasured.ThetreatmentwithAPsoratorvastatininducedaremarkablereductionintheatheroscleroticlesionsandhepaticsteatosisanddecreasedthelevelsoflow-densitylipoprotein,triglyceride,CCL-2andVCAM-1levelsintheplasma.Conversely,theAPssignificantlyincreasedtheplasmalevelsofhigh-densitylipoprotein(HDL)cholesterolandmarkedlyup-regulatedtheglutathioneperoxidase(GPx),catalase(CAT)andsuperoxidedismutase(SOD)levelsinlivertissues.Moreover,theAPstreatmentmodulatedlipidmetabolismbyup-regulatingthetranscriptionofassociatedhepaticgenesincludingPPAR,whiledown-regulatingthetranscriptionofSCAPanditsdownstreamgenesassociatedwithlipidsynthesisintheliver.HistologicalassessmentshowedthattheAPstreatmentalsoreducedthemacrophageinfiltrationintheNutrients2015,77086aorticrootplaqueandtheinflammatorycellsinfiltrationstothelivertissues.Moreover,weconfirmedthattheAPstreatmentgreatlyreducedtheox-LDL-inducedendothelialdysfunctionandmonocyteadhesiontorataorticendothelialcells(RAECs).Mechanistically,theAPstreatmentsuppressedtheROS/MAPK/NF-Bsignalingpathway,andconsequently,reducedCCL-2,ICAM-1andVCAM-1expression.OurresultssuggestthattheAPsareabeneficialnutritionalsupplementfortheattenuationofatherosclerosis.Keywords:applepolyphenols;western-typediet;atherosclerosis;hepaticsteatosis;atorvastatin;oxidativestress;vascularInflammation;ApoE
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mice1.Introduction“Anappleadaykeepsthedoctoraway”.Epidemiologicalevidencessupporttheideathatappleconsumptionisassociatedwithareductionincardiovascularrisk,partiallyduetothepotentanti-oxidativeeffectsofapplepolyphenols(APs)[1].Forcomparison,ascomprisingthemostcommongroupofplantpolyphenols,theflavonoidsexertpotentanti-oxidantandanti-inflammatoryeffects[2–4].Thebeneficialeffectsofflavonoidsonatherosclerosis,includingprotectionagainstthefreeradicals-inducedtissuedamage,havebeenproveninvariousmedicalandchemicalstudies[1–5].ThemainactiveconstituentsoftheAPsincludephloridzin,phlorizin,quercetin,catechins,procyanidins,epicatechin,rutin,andchlorogenicacid[5].TheAPsarenowreceivinginterestfromscientistsandconsumersasdietarysupplementsduetotheirvariousbeneficialeffectsonhumanhealthaseffectivedietarysupplements[6].Moreimportantly,toxicologicalinvestigationshaveconfirmedthattheAPsaresafeandhavelittletoxicityataveragedietarylevel[7].Bothatherosclerosisandnonalcoholicsteatohepatitis,whichwasformerlyconsideredalipid-storagedisease,actuallyinvolvesongoinginflammatoryresponses.Inflammationinthearterialvesselwallisconsideredtoplayanimportantroleinthepathogenesisofatherosclerosis.Indeed,recentadvanceshaveestablishedafundamentalroleforinflammationinmediatingallstagesofthisdisease,frominitiationthroughprogression[8–10].Theactivationofmonocytesandmacrophagesisanimportantinitialstepinthecascadeofeventsthatleadstomanyacuteandchronicinflammatorydiseasesincludingatherosclerosisandnonalcoholicsteatohepatitis.Itisbelievedthattheformationoffoamcells,whicharelipid-ladenmacrophages,isanearlyhallmarkofatheroscleroticlesionformation.Inhumans,ongoinginflammatoryreactionswithinthecoronaryatheroscleroticplaquesareincreasinglythoughttobecrucialdeterminantsoftheclinicalcourseofpatientswithcoronaryarterydiseases[11,12].Likewise,inavariousofanimalmodelsofatherosclerosisandnonalcoholicsteatohepatitis,signsofinflammationarecloselyassociatedwiththeincipientlipidaccumulationinthearterywall[13–15].Atheroscleroticplaquestendtoformparticularlyattheinnercurvaturesandbranchpointsofarteries,regionsthatareoftenassociatedwithdisturbedbloodflow.Theformationisalsoenhancedbyotherfactorssuchasahighplasmalow-densitylipoprotein(LDL)concentration[16].Themechanicalforcesassociatedwithbloodflowhaveaprofoundeffectontheproperti