向日葵對(duì)ApoE-小鼠動(dòng)脈粥樣硬化的作用及機(jī)制

EffectandMechanismofHelianthusAnnuusLonAtherosclerosisinApoE-/-Mice

Abstract

Background:Atherosclerosisisachronicmulti-factordisease,thetreatmentofanti-asisalong-term,evenlifelongprocess.Increasedmacrophageandfoamcellapoptosisduringearlyatherosclerosisretardsplaqueprogressionbyimpedingfoamcellformation,suppressinginflammationandlimitinglesioncellularity.Plant-deriveddrugsmaybeagoodchoice.Therefore,weaimedtoelucidatetheeffectofHelianthusAnnuusL(HAL)onatherosclerosisandtheunderlyingmechanismassociatedwithit.

Methods:Inthisstudy,408-week-oldapolipoproteingeneEKO/KO(ApoE-/-)micewererandomlydividedinto3groupsaccordingtobodyweight.Onegroupwasfedanormaldiet,twogroupswerefedahigh-fatdiet,andthreegroupswerefedahigh-fatdietand5%HelianthusAnnuusL.powder(HLP).Thecontentofproteinandfatwasthesamein2and3groups.Micewerefedfor24weeksinSPFbarrier.

Results:

Conclusion:OurdatashowsthatHLPinhibitsfoamcellformation,aswellaspromotesmacrophageandfoamcellapoptosisby.Thesefindingsprovidenovelmechanisticinsightintotheanti-atherogenicpotentialofHAL,whichmayprovebeneficialagainstearly-stageatheroscleroticlesions.

Keywords:Atherosclerosis,Macrophages,Foamcells,HelianthusAnnuusL,ApoE-/-mice,MIF,IL-1β,TNF-a,IL-6,IL-10

Introduction

Atherosclerosis,alipid-driveninflammatorydiseaseofthearterialwall,istheunderlyingcauseofthemajorityofcardiovasculardiseases(CVD)

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[1]

.CVDisresponsibleforoneinthreeglobaldeathsandposesasubstantialeconomicburden

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[2,3]

.AtherosclerosisistheprimarycauseunderlyingCVD-relatedmorbidityandmortality

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[2,3]

.Itisachronicinflammatorydiseaseofthevasculaturefeaturingslowonsetwithamarkedincreaseintheelderlypopulation

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[2,3]

.Atherosclerosisischaracterizedbytheformationofatheroscleroticplaqueinthesub-endothelialspacethatcomprisesofmigratedsmoothmusclecells(SMCs),oxidizedlipids,apoptoticmacrophages,foamcells,activatedleukocytes,andinflammatorycytokines

ADDINEN.CITE<EndNote><Cite><Author>Lusis</Author><Year>2000</Year><RecNum>9</RecNum><DisplayText><styleface="superscript">[4]</style></DisplayText><record><rec-number>9</rec-number><foreign-keys><keyapp="EN"db-id="vzrxtt9ty90ewtedaeuprfx5tp50rsderw5t"timestamp="1576853041">9</key><keyapp="ENWeb"db-id="">0</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Lusis,A.J.</author></authors></contributors><auth-address>DepartmentofMedicine,BiologyInstitute,UniversityofCalifornia,LosAngeles90095,USA.jlusis@</auth-address><titles><title>Atherosclerosis</title><secondary-title>Nature</secondary-title></titles><periodical><full-title>Nature</full-title></periodical><pages>233-41</pages><volume>407</volume><number>6801</number><edition>2000/09/23</edition><keywords><keyword>Animals</keyword><keyword>*Arteriosclerosis/diagnosis/drugtherapy/etiology/genetics/pathology</keyword><keyword>CoronaryDisease/etiology</keyword><keyword>Humans</keyword><keyword>RiskAssessment</keyword></keywords><dates><year>2000</year><pub-dates><date>Sep14</date></pub-dates></dates><isbn>0028-0836(Print) 0028-0836(Linking)</isbn><accession-num>11001066</accession-num><urls><related-urls><url>/pubmed/11001066</url></related-urls></urls><custom2>PMC2826222</custom2><electronic-resource-num>10.1038/35025203</electronic-resource-num></record></Cite></EndNote>

[4]

.Theprogressionofatherosclerosisislargelydeterminedbycommonmodifiableriskfactors(e.g.dyslipidemia,smoking,hypertension,diabetes,obesity)andvariousunmodifiablefactors(e.g.age,malegender,ethnicityandgeneticpredispositionsuchasfamilialhypercholesterolemia(FH)andTangierdisease

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[5,6]

.Themostimportantcausalagentsofatherosclerosisareapolipoprotein(apo)B-containinglipoproteinsofwhichlow-densitylipoprotein(LDL)haslongbeenregardedastheprincipledriverfortheinitiationandprogressionofatheroscleroticplaques

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[2,3,5,6]

.Indeed,amorerecentevaluationofevidencefromarangeofmeta-analysesofgenetic,epidemiologicalandclinicalstudiesdemonstratedanunequivocalcausalitybetweenLDL-cholesterol(LDL-C)andatherosclerosis-associatedCVD

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[7]

.

AlthoughprimaryandsecondarypreventivestrategieshavesignificantlyloweredtheincidenceofCVD,atherosclerosisremainsamajorcauseofmorbidityandmortality

ADDINEN.CITE<EndNote><Cite><Author>Patel</Author><Year>2018</Year><RecNum>7</RecNum><DisplayText><styleface="superscript">[8]</style></DisplayText><record><rec-number>7</rec-number><foreign-keys><keyapp="EN"db-id="vzrxtt9ty90ewtedaeuprfx5tp50rsderw5t"timestamp="1574950502">7</key><keyapp="ENWeb"db-id="">0</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Patel,K.V.</author><author>Pandey,A.</author><author>deLemos,J.A.</author></authors></contributors><auth-address>DepartmentofInternalMedicine,DivisionofCardiology,UniversityofTexasSouthwesternMedicalCenter,Dallas. DepartmentofInternalMedicine,DivisionofCardiology,UniversityofTexasSouthwesternMedicalCenter,Dallas.james.delemos@.</auth-address><titles><title>ConceptualFrameworkforAddressingResidualAtheroscleroticCardiovascularDiseaseRiskintheEraofPrecisionMedicine</title><secondary-title>Circulation</secondary-title></titles><periodical><full-title>Circulation</full-title></periodical><pages>2551-2553</pages><volume>137</volume><number>24</number><edition>2018/04/13</edition><keywords><keyword>Atherosclerosis/*therapy</keyword><keyword>Evidence-BasedMedicine/*methods/trends</keyword><keyword>Humans</keyword><keyword>PrecisionMedicine/*methods/trends</keyword><keyword>RiskFactors</keyword><keyword>*atherosclerosis</keyword><keyword>*biomarkers</keyword><keyword>*precisionmedicine</keyword><keyword>*residualrisk</keyword><keyword>*secondaryprevention</keyword></keywords><dates><year>2018</year><pub-dates><date>Jun12</date></pub-dates></dates><isbn>1524-4539(Electronic) 0009-7322(Linking)</isbn><accession-num>29643058</accession-num><urls><related-urls><url>/pubmed/29643058</url></related-urls></urls><electronic-resource-num>10.1161/CIRCULATIONAHA.118.035289</electronic-resource-num></record></Cite></EndNote>

[8]

.Additionaltherapeuticstrategies,whichtargettheresidualcardiovascularriskthatpersistsafteroptimalpharmacologicaltreatment,arethereforerequired

ADDINEN.CITE<EndNote><Cite><Author>Patel</Author><Year>2018</Year><RecNum>7</RecNum><DisplayText><styleface="superscript">[8]</style></DisplayText><record><rec-number>7</rec-number><foreign-keys><keyapp="EN"db-id="vzrxtt9ty90ewtedaeuprfx5tp50rsderw5t"timestamp="1574950502">7</key><keyapp="ENWeb"db-id="">0</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Patel,K.V.</author><author>Pandey,A.</author><author>deLemos,J.A.</author></authors></contributors><auth-address>DepartmentofInternalMedicine,DivisionofCardiology,UniversityofTexasSouthwesternMedicalCenter,Dallas. DepartmentofInternalMedicine,DivisionofCardiology,UniversityofTexasSouthwesternMedicalCenter,Dallas.james.delemos@.</auth-address><titles><title>ConceptualFrameworkforAddressingResidualAtheroscleroticCardiovascularDiseaseRiskintheEraofPrecisionMedicine</title><secondary-title>Circulation</secondary-title></titles><periodical><full-title>Circulation</full-title></periodical><pages>2551-2553</pages><volume>137</volume><number>24</number><edition>2018/04/13</edition><keywords><keyword>Atherosclerosis/*therapy</keyword><keyword>Evidence-BasedMedicine/*methods/trends</keyword><keyword>Humans</keyword><keyword>PrecisionMedicine/*methods/trends</keyword><keyword>RiskFactors</keyword><keyword>*atherosclerosis</keyword><keyword>*biomarkers</keyword><keyword>*precisionmedicine</keyword><keyword>*residualrisk</keyword><keyword>*secondaryprevention</keyword></keywords><dates><year>2018</year><pub-dates><date>Jun12</date></pub-dates></dates><isbn>1524-4539(Electronic) 0009-7322(Linking)</isbn><accession-num>29643058</accession-num><urls><related-urls><url>/pubmed/29643058</url></related-urls></urls><electronic-resource-num>10.1161/CIRCULATIONAHA.118.035289</electronic-resource-num></record></Cite></EndNote>

[8]

.Inadditiontodyslipidaemia,immunecellactivationandsubsequentinflammationdriveatherogenesis

ADDINEN.CITE<EndNote><Cite><Author>Kyaw</Author><Year>2017</Year><RecNum>8</RecNum><DisplayText><styleface="superscript">[9]</style></DisplayText><record><rec-number>8</rec-number><foreign-keys><keyapp="EN"db-id="vzrxtt9ty90ewtedaeuprfx5tp50rsderw5t"timestamp="1574950978">8</key><keyapp="ENWeb"db-id="">0</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Kyaw,T.</author><author>Peter,K.</author><author>Li,Y.</author><author>Tipping,P.</author><author>Toh,B.H.</author><author>Bobik,A.</author></authors></contributors><auth-address>BakerHeartandDiabetesInstitute,Melbourne,Vic,Australia. DepartmentofMedicine,MonashUniversity,Melbourne,Vic,Australia. DepartmentofImmunology,MonashUniversity,Melbourne,Vic,Australia.</auth-address><titles><title>Cytotoxiclymphocytesandatherosclerosis:significance,mechanismsandtherapeuticchallenges</title><secondary-title>BrJPharmacol</secondary-title></titles><periodical><full-title>BrJPharmacol</full-title></periodical><pages>3956-3972</pages><volume>174</volume><number>22</number><edition>2017/05/05</edition><keywords><keyword>Animals</keyword><keyword>Atherosclerosis/*immunology</keyword><keyword>Humans</keyword><keyword>KillerCells,Natural/*immunology</keyword><keyword>T-Lymphocytes/*immunology</keyword></keywords><dates><year>2017</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1476-5381(Electronic) 0007-1188(Linking)</isbn><accession-num>28471481</accession-num><urls><related-urls><url>/pubmed/28471481</url></related-urls></urls><custom2>PMC5660002</custom2><electronic-resource-num>10.1111/bph.13845</electronic-resource-num></record></Cite></EndNote>

[9]

.Macrophagesplayapivotalroleinatherosclerosis,astheyaretheprimarycellstoinvadeatheroscleroticlesionsandingestoxidizedlow-densitylipoprotein(ox-LDL)viascavengerreceptors(SRs)namely,CD36andclassASR(SR-A),toformlipid-ladenfoamcells.Thesefoamcellsinitiateaninflammatorycascadebyreleasingpro-inflammatorycytokinesthatacceleratelipoproteinretentionandvascularinflammation

ADDINEN.CITE<EndNote><Cite><Author>Libby</Author><Year>2011</Year><RecNum>14</RecNum><DisplayText><styleface="superscript">[10]</style></DisplayText><record><rec-number>14</rec-number><foreign-keys><keyapp="EN"db-id="vzrxtt9ty90ewtedaeuprfx5tp50rsderw5t"timestamp="1576860914">14</key><keyapp="ENWeb"db-id="">0</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Libby,P.</author><author>Ridker,P.M.</author><author>Hansson,G.K.</author></authors></contributors><auth-address>CardiovascularDivision,DepartmentofMedicine,BrighamandWomen'sHospital,HarvardMedicalSchool,77AvenueLouisPasteur,Boston,Massachusetts02115,USA.plibby@</auth-address><titles><title>Progressandchallengesintranslatingthebiologyofatherosclerosis</title><secondary-title>Nature</secondary-title></titles><periodical><full-title>Nature</full-title></periodical><pages>317-25</pages><volume>473</volume><number>7347</number><edition>2011/05/20</edition><keywords><keyword>Animals</keyword><keyword>Atherosclerosis/blood/genetics/*pathology/*physiopathology</keyword><keyword>Cholesterol,HDL/metabolism</keyword><keyword>Cholesterol,LDL/metabolism</keyword><keyword>Humans</keyword><keyword>Inflammation/drugtherapy/metabolism</keyword><keyword>LipidMetabolism</keyword><keyword>Triglycerides/metabolism</keyword></keywords><dates><year>2011</year><pub-dates><date>May19</date></pub-dates></dates><isbn>1476-4687(Electronic) 0028-0836(Linking)</isbn><accession-num>21593864</accession-num><urls><related-urls><url>/pubmed/21593864</url></related-urls></urls><electronic-resource-num>10.1038/nature10146</electronic-resource-num></record></Cite></EndNote>

[10]

.Ampleevidenceintheliteraturereportthatmacrophageapoptosisplaysadualroleinatheroscleroticplaquedevelopment.Inearlyfattystreaklesions,macrophageandfoamcellapoptosisisaccompaniedwithefficientefferocytosis,whichlimitslesioncellularity,suppressesinflammation,andplaqueprogression.Conversely,inadvancedlesionsinefficientefferocytosisleadstotheaccumulationofapoptoticmacrophages,whichfavorstheformationofafibrouscapcomprisingofnecroticlipid-richcoreandSMCs,therebypromotinginflammation,plaquedisruptionandthrombosis

ADDINEN.CITE<EndNote><Cite><Author>Seimon</Author><Year>2009</Year><RecNum>15</RecNum><DisplayText><styleface="superscript">[11]</style></DisplayText><record><rec-number>15</rec-number><foreign-keys><keyapp="EN"db-id="vzrxtt9ty90ewtedaeuprfx5tp50rsderw5t"timestamp="1576861546">15</key><keyapp="ENWeb"db-id="">0</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Seimon,T.</author><author>Tabas,I.</author></authors></contributors><auth-address>DepartmentofMedicine,ColumbiaUniversity,NewYork,NY10032,USA.</auth-address><titles><title>Mechanismsandconsequencesofmacrophageapoptosisinatherosclerosis</title><secondary-title>JLipidRes</secondary-title></titles><periodical><full-title>JLipidRes</full-title></periodical><pages>S382-7</pages><volume>50Suppl</volume><edition>2008/10/28</edition><keywords><keyword>Animals</keyword><keyword>*Apoptosis</keyword><keyword>Atherosclerosis/genetics/metabolism/*pathology</keyword><keyword>EndoplasmicReticulum/metabolism</keyword><keyword>Macrophages/*cytology/metabolism</keyword><keyword>Receptors,PatternRecognition/metabolism</keyword></keywords><dates><year>2009</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0022-2275(Print) 0022-2275(Linking)</isbn><accession-num>18953058</accession-num><urls><related-urls><url>/pubmed/18953058</url></related-urls></urls><custom2>PMC2674693</custom2><electronic-resource-num>10.1194/jlr.R800032-JLR200</electronic-resource-num></record></Cite></EndNote>

[11]

.

Therefore,noveltherapeuticapproacheswhichcanreducefoamcellformationandenhancemacrophageandfoamcellapoptosisintheearlystageofplaquedevelopment,needtobeimplementedforpreventingtheprogressiontoadvancedlesions.Presently,syntheticanti-hyperlipidemicdrugslikestatinsarewidelyusedfortreatingcardiovasculardisorders;however,thesedrugsareassociatedwithconsiderableresidualriskforCVDtogetherwithvarioussideeffects

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[1,2]

.This,togetherwithmanypromisingpharmaceuticalleadsfailingattheclinicallevel,hasfuelledsubstantialinterestinharnessingthepotentialofnutraceuticalsinthepreventionofatherosclerosisandtheiruseasadd-onswithcurrentpharmaceuticalagents[1-2,11].Inthisregard,manyrecentstudieshavehighlightedthepromiseofnaturaldrugs.theanti-atherosclerosiseffectofnaturaldrugshasgraduallyemergedandattractedpeople'sattention.Somespecificflavonoidshavesignificanteffectsonanti-atherosclerosis.Therefore,analternativesystemofmedicinelikeAyurvedaadvocatestheuseofvariousmedicinalplants,andonesuchplantisHelianthusAnnuusL(HAL),whichexhibitsanti-inflammatory,anti-oxidantandhypolipidemicactivities[].Basedonthefactthatthemaincomponentsofthedrugareflavonoidsandpolysaccharides,thedrugmayalsohaveagoodeffectonthepreventionandtreatmentofatherosclerosis,whichwillprovidereferenceforfurtherresearchandapplicationvalueofthedrug.

Materialandmethods

Preparationoffodder

TheHelianthusAnnuusL.powder(HAP)werecollectedfromHelianthusAnnuusGrowinginsaline-alkalifields.ForthepreparationofHAPtheHelianthusAnnuuswereRemovedseeds,driedandcoarselypowdered.Further,HAPwerestoredinthedark,at0?4°Cforsubsequentexperiments.

(1)ordinaryfeed:each1000goffeedcontains199gcrudeprotein,60gcrudefat,52gcrudeash,306.25gcornstarch,79.12gmaltodextrin,125.93gsucrose,19gcellulose,mineralmixtureM100211.14g,calciumphosphate14.49g,calciumcarbonate6.13g,potassiumcitrate18.39g,vitaminmixtureV100111.14g,hydrocholinetartrate2.23g,water90.4g.

(2)High-fatfeed:H10540formula,each1000gfeedcontains222.88gcasein,3.34gcysteine,236.25gcornstarch,79.12gmaltodextrin,125.93gsucrose,55.72gcellulose,27.86gsoybeanoil,172.73gcocoabutter,mineralmixtureV100111.14gvitaminmixture,2.23ghydrocholinetartrateand12.54gcholesterol.

(3)HALhigh-fatfeed:Each1000goffeedcontained218.38gofcasein,3.34gofcysteine,202.85gofcornstarch,79.12gofmaltodextrin,125.93gofsucrose,46.87gofcellulose,24.61gofsoybeanoil,172.73gofcocoabutter,M100211.14gofmineralmixture,14.49gofcalciumphosphate,6.13gofcalciumcarbonate,18.39gofpotassiumcitrate,V100111.14gofvitaminmixture,2.23gofhydrocholinetartrate,12.54gofcholesterol,Sunflowerdiscpowder50g(containing4.5gprotein,3.25gfat,8.85gcellulose,24.45gnitrogen-freeextract,5.05gash,1.5gpectin,2.4gothers).

fodderwerestoredinthedark,at0?4°Cforsubsequentexperiments.

EstablishmentofatherosclerosismodelinApoE-/-mice

EightyhealthySPFfemaleApoE-/-micewereselected,weighedafter1weekofnormalfeeding,fastedfor12hoursbeforemodeling,andstartedtheexperimentafterthemiceweightwasrecorded.Afterweightstratification,themicewererandomlydividedinto3groups:20miceingroup1weregivenordinarydiet,namelythecontrolgroup;40miceingroup2weregivenhigh-fatdiet;20miceingroup3weregivenhigh-fatdietand5%sunflowerplatepowder.Weighmiceandfoodconsumptionweekly.Foodintakewasmeasuredandweighedat24weeksinthemetaboliccage.After12hoursoffasting,isofluranewasinhaledandanesthetizedtocollectsamplesfrommice.Bloodsamplesweretakenaftereyeballremoval,andsamplesofaorta,heart,liver,spleen,perirenalfat,colon,fecesandskintissuesweretaken,andcorrespondingexperimentswereconducted.

Generalconditionofmice

Duringthemodelingperiod,theweightofeachgroupofmicewastestedweekly.Afterthemodeling,foodintake,heartweight,Lee'sindex,liverindexandspleenindexofeachgroupwereinvestigatedat24h.Thespecificcalculationformulaisasfollows:

Lee'sindex=bodyweight(g)^(1/3)/bodylength(cmfromnosetoanus)*1000

Liverindex=liverweightg/bodyweightg

Spleenindex=spleennumbermg/bodyweightg

AortabyHEstaining

After24weeks,allmicewereanesthetizedwithisoflurane,andtheaortaofeachgroupwasfixedwithformalinsolution.Afterwashing,dehydration,paraffinembedding,sectioning,dryingandstaining,theaortaofeachgroupwasstainedwithHE,andthepathologicalchangesoftheaortaofeachgroupwereobserved.

AortabyoilredO（ORO）staining

After24weeks,allmicewereanesthetizedwithisoflurane,aortictissueofeachgroupwascollected,andtheaorticlipidcontentofthewholegroupwasobservedbyoilredOstaining.Inaddition,theaortawasfrozensectionandoilredOstainingwasperformedtoobservethelipidchangesintheactivevascularlumen.

Serumbiochemicaltest

After24weeks,allmicewereanesthetizedwithisofluraneandcollectedserumfromeachgroup.SerumlevelsofTC,TG,LDLandHDLweredetected.

Activityofantioxidantfactorsinaortictissue

After24weeks,allmicewereanesthetizedwithisoflurane,andthenaortictissuesofeachgroupwerecollected.Afteraccuratelyweighing50mgaortictissues,450lsalinewasaddedandthenultrasoniccrushingwasperformed.Aftercentrifugationat3000rpmfor10min,10%tissuehomogenatewasprepared.

Serumlevelsofinflammatoryfactorsweremeasured

After24weeks,allmicewereanesthetizedwithisoflurane,andtheserumofeachgroupwascollected.TheserumlevelsofIL-1,TNF-a,IL-10,andIL-6ineachgroupweredetected,andthelevelofNOintheaortichomogenatewasalsodetected.

Geneexpressionofaorticinflammatoryfactorwasdetected

After24weeks,allmicewereanesthetizedwithisoflurane,andtotalRNAwasextractedfromtheaortictissuesofthemiceineachgroup.MRNAexpressionsofil-1mRNA,tnf-amRNAandil-6mRNAintheaortictissuesofthemiceineachgroupweredetectedbyqPCR(table1forprimersequences).

Statisticalanalysis

Dataareexpressedinmean±SD.Thesignificanceofmeanvaluesofdifferentparametersbetweenthetreatmentgroupswasanalyzedusingone-wayanalysisofvariances(ANOVA)followedbypost-hocTukeytest.Pvalues<0.05wereconsideredtobestatisticallysignificant.AllthestatisticalanalysiswasperformedusingGraphPadPrism(version6,California,USA).

Results

PhytochemicalanalysisofHAP

Mainnutrients:crudeprotein7%~9%,crudefat6.5%~10.5%,crudefiber17.1%,nitrogenfreeextract43.9%,crudestarch40.0%~48.9%,pectin2.4%~3.0%,graypowder10%.

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