The Role of OxLDL in Atherosclerosis

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Hindawi Publishing CorporationMediators o In ammationVolume , Article ID , pageshttp://dx.doi.org/ . / /

Review ArticleThe Role of Oxidized Low-Density Lipoproteins in Atherosclerosis: The Myths and the Facts

Giuseppe Maiolino, Giacomo Rossitto, Paola Caielli, Valeria Bisogni,Gian Paolo Rossi, and Lorenzo A. CalDepartment of Medicine (DIMED), Internal Medicine , University of Padova, Via Giustiniani , Padova, Italy

Correspondence should be addressed to Lorenzo A. Cal o; [email protected]

Received June ; Accepted August

Academic Editor: Ishak ekin

Copyright Giuseppe Maiolino et al. Tis is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Te oxidative modi cation hypothesis o atherosclerosis, which assigns to oxidized low-density lipoproteins (LDLs) a crucialrole in atherosclerosis initiation and progression, is still debated. Tis review examines the role played by oxidized LDLs inatherogenesis taking intoaccount dataderivedby studiesbasedonmolecularand clinical approaches.Experimental datacarriedoutin cellular lines and animal models o atherosclerosis support the proatherogenic role o oxidized LDLs: (a) through chemotacticand proli erating actions on monocytes/macrophages, inciting their trans ormation into oam cells; (b) through stimulation o smooth muscle cells (SMCs) recruitment and proli eration in the tunica intima; (c) through eliciting endothelial cells, SMCs, andmacrophages apoptosis with ensuing necroticcore development.Moreover,mosto the experimental dataon atherosclerosis-proneanimals bene ting rom antioxidant treatment points towards a link between oxidative stress and atherosclerosis. Te evidencecoming rom cohort studies demonstrating an association between oxidized LDLs and cardiovascular events, notwithstandingsome discrepancies, seems to point towards a role o oxidized LDLs in atherosclerotic plaque development and destabilization.Finally, the results o randomized clinical trials employing antioxidants completed up to date, despite demonstrating no bene ts inhealthy populations, suggest a bene t in high-risk patients. In conclusion, available dataseem to validate the oxidative modi cationhypothesis o atherosclerosis, although additional proo s are still needed.

1. Introduction

Recent postulates on atherosclerosis designate the appear-ance o qualitative changes on endothelial cells, triggeredby irritative stimuli (e.g., hypertension, dyslipidemia, andcigarette smoking), as an early pathogenic event [ ]. Tisprocess occurs at speci c segments o the arterial tree,mainly branching points and bi urcations, characterized by disturbed laminar blood ow, probably owing to differencesin arteries regional development [ ] and to the loss o theatheroprotective effect o laminar shear stress [ ]. In thissetting, the endothelium expressesadhesion and chemotacticmolecules and acquires an increased permeability to macro-molecules, which modi es the composition o the suben-dothelial extracellular matrix. Hence, the entryo low-density lipoprotein (LDL) particles in the arterial wall ollowed by their retention through the binding o apolipoprotein B

to proteoglycans o the extracellular matrix [ ] is held tobe a key-initiating actor in early atherogenesis [ ]. TeLDL particles trapped in the subintimal extracellular matrixare mildly oxidized by resident vascular cells [ ]. Tey retain the capability o binding to the LDL receptor [ , ]and to exert their proatherogenic effects [ ], includingstimulation o the resident vascular cells to produce mono-cyte chemotactic protein- , granulocyte, and macrophagecolony-stimulating actors. Tese molecules promote mono-cytes recruitment and their differentiation intomacrophages,which are able to urther promote the oxidation o LDLs[ ] through myeloperoxidase and reactive oxygen species.Completely oxidized LDLs, characterized by an increasedapolipoprotein B negative charge, are recognized by scav-enger receptors on macrophages and internalized to orm

oam cells [ ], the hallmark o the atherosclerotic lesion.Furthermore, macrophages play a key role in atherogenesis
http://dx.doi.org/10.1155/2013/714653http://dx.doi.org/10.1155/2013/714653


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Mediators o In ammation

Endothelialdysfunction

NOS Permeability Adhesion molecules Chemoattractants

HypertensionDyslipidemiaCigarette smokingDiabetes

Trapping andmild oxidation

Monocytes

Macrophage

Proteoglycans

LDL

OxLDL

Scavengerreceptors

SMCs migration Proliferation Collagen synthesis

Inammation ptls adhesion Lymph

+

+

+

+

+

+

PDGF b F G F

MMPs

G - C S F M - C S F

M C P - 1

Intima

SMC

EC

T lymphocytes

LipidsCell debrisLysosomal enzymes

Fibrous cap

ROS

Apoptosis

Foam cell

Entry

F : Putative pathway o oxidized low-density lipoprotein (oxLDL) in the atherogenetic process according to the oxidative hypothesiso atherosclerosis.

through their proin ammatory action, which involves theproduction o interleukin- and tumor necrosis actor (Fig-ure ).

Other main effectors in the development o atheroscle-rotic lesions are smooth muscle cells (SMCs), which arerecruited rom the tunica media to the subendothelial space,where they proli erate in response to mediators such as theplatelet-derived growth actor. SMCs residing in the tunicaintima produce extracellular matrix molecules, or example,interstitial collagen and elastin, and build the brous cap thatoverlies the growing atherosclerotic plaque. Te latter entailsmacrophage-derived oam cells, cellular debris, and extracel-lular lipids, which are inefficiently cleared due to de ectiveefferocytosis and thereby orm the so-called necrotic core o the plaque [ ].

Te atherosclerotic plaque becomes clinically mani estwhen it reaches an advanced stage due to its blood ow-limiting effects or itsdestabilization withensuing thrombosis.Un ortunately, the latter complication, which is responsible

or ischemic events, is not strictly related to the degreeo stenosis at angiography [ , ] as its occurrence standsmostly on the cellular eatures o the plaque and particularly on the thickness o the overlying brous cap [ , ]. In act,atherosclerotic plaques prone to rupture are characterized by accumulation o in ammatory cells, mostly at the shoulderregions. Tese cells degrade collagen through release o collagenolytic enzymes, mainly matrix metalloproteinases

(MMPs), and also reduce its synthesis by inducing SMCsapoptosis [ ].

Many excellent reviews on the current knowledge o atherosclerosis are available, but ew are ocused on oxidizedLDLs. Hence, this review examines the role played by oxi-dized LDLs in atherogenesis taking into account data derivedby studies based on molecular and clinical approaches.

2. Evidence Linking Oxidized LDLsto Atherosclerosis

Te oxidative modi cation hypothesis designates the oxida-tive change o LDLs as a crucial, i not mandatory, stepin atherogenesis [ ]. Tis theory originated rom studiesdemonstrating that LDLs modi ed by endothelial cells,trans ormation entailing an oxidation process [ ], could beinternalized and accumulated avidly by macrophages [ , ],leading to oam cell ormation, although these cells couldalso be generated rom macrophages internalizing nativeLDLs rom themediumthrough micropinocytosis [ ],orby uptake o aggregated LDLs or LDL immune complexes.

Several potential mechanisms can explain how LDLoxidative modi cation occurs within the arterial wall in vivo.A major role has been proposed or the / -lipoxygenase[ , ] because ( ) it is expressed in atherosclerotic plaquesbut not in normal vessels [ ] and ( ) its inhibition was


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associated with decreased oxidation o LDLs [ ] andreduced atherosclerosis in animal models [ , , ].Myeloperoxidase, a heme enzyme secreted by neutrophilsand monocytes/macrophages, is another suggested agent.It was ound in human atherosclerotic plaques [ ] andmodi es LDLs, thus increasing their affinity or CD and

SR-A [ , ], the scavenger receptors mediating the uptakeo oxidized LDLs by macrophages. Nitric oxide synthase(NOS) and nicotinamide adenine dinucleotide phosphate(NADPH)-oxidase are other putative players as their prod-ucts nitric oxide and superoxide anion, respectively, cancombine to orm the strong oxidizing agent peroxynitrite.

Native LDLs are internalized by macrophages at a pacetoolowto account or oam cells ormation[ ] owing toLDLreceptor downregulation. Oxidative modi cation o LDLsincreases their uptake by macrophages [ ], via scavengerreceptors. Te latter are not downregulated in response toincreased intracellular cholesterol, which explains why oamcells ormation is held to occur with oxidized LDLs and notwith native LDLs.

Besides contributing to the ormation o lipid-ladenmacrophages, oxidized LDLs exhibit a wide array o biologi-cal properties, which are deemed to promote atherosclerosis.

(i) Oxidized LDLs exert chemotactic activity or mono-cytes [ ], stimulate their binding to endothelial cells[ ] by inducing the expression o intercellular adhe-sion molecule- and vascular-cell adhesion molecule-

[ ], are mitogenic or macrophages [ ], andpromote their trapping in the intima, while limitingtheir egress rom the arterial wall [ ]. Hence, oxLDLis key or recruitment, activation, and proli eration o monocytes/macrophages in the arterial wall.

(ii) Oxidized LDLs increase the expression o growth ac-tors, such as platelet-derived growth actor (PDGF)and basic broblast growth actor (FGF) by endothe-lial cells and macrophages. Te ormer stimulatesmigration o SMCs [ ], while the latter inducesSMCs proli eration [ ].

(iii) Oxidized LDLs stimulate collagen production by SMCs [ ], thus contributing to the brous cap liningthe atherosclerotic plaque and the expansion o thelesion size. However, they could also promote brouscap thinning by increasing secretion o matrix met-alloproteinase [ ] and matrix metalloproteinase

, decreasing production o the tissue inhibitor o metalloproteinase [ ], and inducing SMCs apop-tosis [ ]. Tere ore, they can contribute to theoccurrence o vulnerable plaques [ , ]. Hence,taken together, this evidence involved oxidized LDLsin the progression o the atherosclerotic plaque andthe development o its complications.

(iv) Oxidized LDLs are cytotoxic to vascular cells [ , ]and promote their apoptosis [ , ] with ensuingrelease in the subendothelial space o lipids andlysosomal enzymes, enhancing the progression o theatherosclerotic plaque [ ] and the production o thenecrotic core.

(v) Oxidized LDLsstimulateplatelet adhesion and aggre-gation, by decreasing endothelial production o nitric oxide, increasing prostacyclin production [ ,

], and stimulating the synthesis o prostaglandinsand prostaglandin precursors [ ]. Moreover, they decrease the secretion o the tissue-type plasminogen

activator and increase that o plasminogen activatorinhibitor- ollowed by a reduction o the brinolyticactivity o endothelium [ ]. Ultimately, they may determine vasoconstriction by inhibiting nitricoxide [ ] and increasing endothelin production[ ]. aken together, these ndings may explain thethrombotic complications o advanced atheroscle-rotic plaques.

3. In Vivo Models Supporting the OxidizedLDL Role in Atherosclerosis

Several studies were carried out in vivo in animal modelswhere eithera modulation o oxidative stressor manipulationo the scavenger receptor was undertaken, in order to provethe role o oxidized LDLs in the pathogenesis o atheroscle-rosis.

In an animal model o increased oxidative stressobtainedthrough the overexpression o -lipoxygenase in the vas-cular wall, larger atherosclerotic lesions were ound inLDL receptor-de cient mice [ ]. However, a decreasedatherosclerosis in cholesterol- ed rabbits and WHHL rabbitswhose macrophages overexpressed human -lipoxygenasewas also reported [ ]. Animal models o reduced oxidativestress, instead, were obtained through knockout o oxidativestress-related genes or increasing the antioxidants: in threedifferent knockout mouse models or / -lipoxygenase,a decreased severity o atherosclerosis was seen [ ,

]. However, in apoE-de cient mice, the knocking outo the macrophage-speci c / -lipoxygenase increased theextension o atherosclerotic lesions [ ].

Te knockout in atherosclerosis-prone mice models o either SR-A or CD scavenger receptors, accounting oralmost % o macrophage oxidized LDLs uptake [ ], wasdemonstrated to be efficacious in decreasing the atheroscle-rotic burden [ , ]. However, these results were notcon rmed in another mice model with a CD and SR-Adouble knockout [ ].

Te results o these studies proved to be highly contra-dictory, due to the different animal models used, the differentgenetic background, and the unexpected consequences o gene deletions [ ].

Finally, in spite o these con icting data, support tothe oxidative theory comes rom extensive literature on thetreatmento atherosclerosis-prone animals with antioxidants(reviewed by Witztum and Steinberg [ ]). Most o thesestudies were carried out with probucol and demonstrated aprotection rom atherosclerotic lesions with the exception o the murine models, possibly secondary to a peculiar toxicity o this molecule in mice. In act, in apoE-de cient mice edwith vitamin E, decreased atherosclerosis, paralleled with adecrease o aortic wall, plasma, and urinary F2 isoprostanes,a marker o oxidative stress, was observed [ ].


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4. Human Findings Supporting the OxidizedLDLs Role in Atherosclerosis

Tere is a wealth o literature on the association between oxi-dized LDLs andcardiovascular events. An important premiseneeds to be made be orehand, however, in that oxidation o

LDLs induces immunogenic epitopes in their particles [ ]with ensuing generation o antibodies against them (oxLDLAbs). Since these autoantibodies are detectable in the sera o the majority o patients with advanced atherosclerotic lesions[ ], they can be viewed as in vivo markers o LDL oxidation.Oxidized LDLs and their involvement in atherosclerosis canthere ore be assessed by two ways: ( ) using murine mon-oclonal antibodies directed toward different oxidized LDLsepitopes and ( ) determining the immunogenic response tooxidizedLDLs.Both approaches have advantages and pit alls,as reviewed in detail by simikas [ ].

Human studies on the association o oxidized LDLswith atherosclerosis or cardiovascular events have beenhighlycon icting ( or rev.[ ]). Some cross-sectionalstudiessuggested a direct association o oxidized LDLs or oxLDLAbs with atherosclerosis in different vascular beds [ , ,

], whereas others ound no association with coronary atherosclerotic burden in coronary artery disease patients[ ]. Owing to these contradictory results, we ocusedon cohort studies, which are more solid and less prone toserendipitous ndings,because o a lowerchance orselectionand recall bias [ ].

Among the twenty-two cohort studies reporting on car-diovascular events, ourteen were positive [ , ] ( able) and eight were negative [ , ] ( able ). Due to

potential publication bias, the preponderance o positiveresults clearly does not provide a proo o the strength o the association [ ]. However, it is important to highlightthat three [ , , ] out o eight negative studies werecompleted in healthy people. Tis carries a limitation in thatthe robustness o cohort studies depends on the assumptionthat the control groupin this case those exposed to low levels o oxidized LDLshas eatures as close as possibleto the group exposed to high levels o oxidized LDLs [ ,

]. Teoretically, this goal can be better accomplishedin selected populations made o patients with similar risk pro le, rather than in studies recruiting healthy persons.Among these negative studies, the rst one reported oncardiovascular events in a large cohort o more than threethousand elderly patients who had cardiovascular eventsafer years o ollowup [ ]. Oxidized LDLs were predictiveo cardiovascular events only i a multivariate analysis wasnot adjusted or the presence o metabolic syndrome. In thesecond study, which enrolled almost three thousand healthy subjects, malonyldialdehyde-LDL autoantibodies were notassociated with cardiovascular events [ ]. In the latter, sim-ilarly per ormed in a healthy population, malonyldialdehyde-and Cu-LDL autoantibodies and oxidized LDLs were notpredictive o progression o carotid atherosclerosis [ ].

Te lack o association between oxidized LDLs andcardiovascular events, possiblydueto lacko statistical power,was also reported in two small cohorts o high-risk end-stagerenal disease [ ] and diabetes mellitus patients [ ].

Other negative studies enrolling patients with coronary heart disease [ , , ] were either too small [ , ] andwith a number o cardiovascular events too low to allow detection o any effect o oxidized LDLs or had an endpointnot appropriate to study atherosclerosis because most o thecardiovascular events were coronary artery restenosis ( %

o total events) [ ]. Moreover, it is worth highlighting thatthe negative study published by simikas et al. [ ] wason the same cohort where an association between coronary artery atherosclerosis and oxidized LDLs was demonstrated[ ].

Among the positive studies our out o ourteen werecarried out in a healthy cohort [ , , , ], thus exposingthem to the same considerations expressed above. Moreover,it has to be pointed out that three o these studies werecompleted in the same cohort, the Brunick study, at differenttime points o ollow up, that is, [ ], [ ], and years[ ], and all demonstrated a predictive value o oxidizedLDLs on cardiovascular events, contradicting the results oncarotid artery atherosclerosis [ ] on the same population.

Other studies demonstrating an association between oxi-dized LDLs and cardiovascular events enrolled small cohortso either high-risk patients [ ] orcoronary artery diseasepatients [ , , ]. Tere ore these positive results couldbe secondary to serendipitous ndings, as suggested by theopposite results on similar cohorts o end-stage renal ailurepatients where high oxLDL Abs titer was associated to eitherlow [ ] or high [ ] cardiovascular mortality.

wo studies reported an association o oxidized LDLswith cardiovascular events in diabetics [ ] and acute coro-nary syndrome patients [ ]. Finally, using a prospectivecohort study design and an unequivocal de nition o thecoronary artery disease phenotype, we reported the associa-tion o oxLDL Abs with cardiovascular mortality and cardiovascular events in more than coronary artery diseasepatients [ ].

In conclusion, most cohort studies reported an associ-ation between oxidized LDLs and cardiovascular events ormortality, in particular those includingeithera veryhigh-risk population, that is, with end-stage renal diseaseand diabetes,or coronary arterydisease patients.However, despitebeinganappealing hypothesis, the oxidation theory o atherosclerosisis not conclusively corroborated by observational studies,which have con icting results, probably owing to the enrol-ment selection criteria and low statistical power.

5. Clinical Trials on Antioxidants andthe Oxidized LDL Hypothesis

Te oxidative theory o atherosclerosiswould be conclusively proven by the bene cial effects o oxidative stress decreaseon cardiovascularevents. Tere ore, the analysis o controlledrandomized trials on antioxidant therapy in this settingis crucial. Te rst report on efficacy o antioxidants oncardiovascular events in coronary artery disease patients[ ] was later con rmed by urther studies [ ] ( able), butnumeroussubsequent randomized clinical trials ailed

to prove any bene t [ ] ( able ). Moreover, meta-analyses on this issue are discordant [ , ].


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: Cohort studies demonstrating an association between oxidized low-density lipoprotein measurement and cardiovascular events.

Oxidative oxLDL test Populationunder study CV endpoints Number o

events Followup Findings Re erence

OxLDL Abs E men IM na years OxLDL predicted IM and carotidplaque progressionWallen eldt et

al. [ ]

OxLDL Abs E subjects CV events CV events years OxLDL predicted CV events simikas et al.[ ]

OxLDL Abs E subjects CV events CV events years OxLDL predicted CV events Kiechl et al.[ ]

OxPL/apoB, AutoAbsMDA-/Cu-oxLDL subjects CV events CV events years

OxPL/apoB predicted CV eventsand stroke; AutoAbs predicted CV

events, stroke, and ACS

simikas et al.[ ]

MDA-LDL NIDDM CV events, MI CVevents, MI . years MDA-LDL predicted MI and CV

eventsLopes-Virella

et al. [ ]

AutoAbs Cu-oxLDL ESRD CV mortality CV deaths months AutoAbs predicted CV mortality Shoji et al. [ ]

AutoAbs Cu-oxLDL ESRD onhemodialysis otal mortality deaths months AutoAbs predicted mortality Bay es et al.

[ ]

AutoAbs Cu-oxLDL ESRD on

hemodialysis CV mortality CV deaths years AutoAbs predicted CV mortality Bay es et al.

[ ]

OxLDL Abs DLH pts with

coronary angiography

CV events:cardiac death,

MI, P CA, andCABG

CV events months OxLDL predicted CV events Shimada et al.[ ]

AutoAbsMDA-oxLDL IHD pts

CV mortality,MI, ACS, and

CV events

CV deaths,CV events . years

OxLDL predicted CV death andevents

Maiolino et al.[ ]

AutoAbs Cu-oxLDL P CA pts,ctr Restenosis restenosis months AutoAbs predicted restenosis Lee et al. [ ]

OxLDL Abs DLH primary P CA pts, ctr Restenosis restenosis months OxLDL predicted restenosis Naruko et al.

[ ]

OxLDL Abs E ACS pts CV death, MI CV deaths,MI years OxLDL predicted MI Johnston et al.[ ]

OxLDL AbsFOH a/DLH

CHF pts (EF< %), ctr

CV death, CVhospitalization,

and atalarrhythmia

CV events days OxLDL predicted CV events sutsui et al.[ ]

Abs: antibodies; ACS: acute coronarysyndrome; AutoAbs:autoantibodies; CABG:coronary arteryby-passsurgery; CHF:congestiveheart ailure; Crt: controls;CV: cardiovascular; ESRD: end-stage renal disease; IHD: ischemic heart disease; IM : intima-media thickness; MI: myocardial in arction; oxLDL: oxidizedlow-density lipoproteins; OxPL/apoB: oxidized phospholipids on apolipoprotein B- ; P CA: percutaneous transluminal coronary angioplasty; pts: patients.

An in depth analysis o these studies, however, high-lighted that most o the negative studies were completedin either healthy or high-risk individuals, whereas resultso clinical trials completed in patients with cardiovasculardisease demonstrated the bene t con erred by antioxidantsin some cases [ , , ], with notable exceptions [ ,

, , ]. Te act that treatment was likely given to thewrong patients, that is, with very low risk pro le, can explainthe ailure o antioxidants trials in preventing cardiovascularevents in the a orementioned negative reports [ ].

Moreover, as in cohort studies, positive effects o antiox-idants were witnessed in randomized trials enrolling very high-risk populations, as end-stage renal disease patients inhemodialysis, characterized by an increased oxidative stress,possibly secondary to hemolysis and hemoglobin-inducedLDL oxidation [ , ]. In these patients, with vitamin E

supplementation, as tested in the SPACE trial randomizingpatients to vitamin E or placebo [ ], cardiovascular eventswere reduced by % and myocardial in arction by %.Accordingly, the potent antioxidant N-acetylcysteine showeda signi cant % decrease in thecombined primaryendpointo cardiovascular events in another study [ ]. Afer theserewarding results, we proposed the use o vitamin E coateddialysis membranein thesepatients,which effectivelyreducesoxidative stress markers [ , ]. Finally, in another high-risk population o diabetics carrying the haptoglobin -genotype, which is associated with in erior antioxidant pro-tection [ ], vitamin E was able to reduce the primary com-posite end pointo cardiovascular death, non atal myocardialin arction, or stroke [ ], even on top o statin therapy [ ].

Tus, most controlled randomized trials involving theuse o antioxidants provided negative results. However,


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: Randomized controlled trials demonstrating no effect o antioxidant therapy.

Source Numbero patientsInclusioncriteria

Antioxidantagent Dose Route Endpoints Followup Events

Virtamo etal. [ ] Male smokers

Vit E,beta-carotene

mg,mg PO

Majorcoronary events (CVdeath, MI)

. y

CV events: Vit E ,beta-carotene , Vit E +

beta-carotene , and pl ; CVdeath: Vit E , beta-carotene, Vit E + beta-carotene ,

and pl ; non- atal MI: Vit E, beta-carotene , Vit E +

beta-carotene , and pl

Rapola et al.[ ] Previous MI

Vit E,beta-carotene

mg,mg PO

Majorcoronary

events (CVdeath, MI)

. y CV events: Vit E ,

beta-carotene , Vit E +beta-carotene , and pl

HA S [ ] CADVit E/C, beta-carotene, and

selenium

IU,g,mg,

and g

PO

Compositeendpoint (CVdeath, MI, andP CA/CABG)

mCV events: antiox , pl ; CV

death: antiox , pl ; non atal MI:antiox , pl

PHS II [ ] Male physicians Vit E/C IUmg POComposite

endpoint (CVdeath, MI, and

stroke)

y CV events: Vit E , pl ; VitC , pl ; CV death: Vit E

, pl ; Vit C , pl ; MI:Vit E , pl ; Vit C , pl

WACS [ ] High CV risk womenVit E/C,

beta-carotene

IUq h,

mg,and

mgq h

PO

Compositeendpoint (CV

death, MI,P CA/CABG,

and stroke)

. y

CV events: Vit E , pl ; VitC , pl ; beta-carotene ,pl ; CV death: Vit E , pl

; Vit C , pl ;beta-carotene , pl ; MI: Vit

E , pl ; Vit C , pl ;beta-carotene , pl

PPP [ ] Subjects RF Vit E mg PO

Compositeendpoint (CVdeath, MI, and

stroke)

. y CV events: Vit E , pl ; CVdeath: Vit E , pl ; MI: Vit E

, pl

GISSI-prevenzione[ ]

Recent MI Vit E mg PO


stroke)


, pl

Greenberget al. [ ] Skin cancer beta-carotene mg PO CV death . y CV death: beta-carotene , pl

PHS [ ] Male physicians beta-carotene mgq PO

Malignantneoplasm;composite

endpoint (CVdeath, MI, and

stroke)

y

CV events: beta-carotene , pl; CV death: beta-carotene, pl ; MI: beta-carotene

, pl

SUVIMAX[ ] Adult subjects

Vit E/C, beta-carotene,selenium,and zinc

mg,mg,mg,

g,and

mg

PO CV ischemicevents . y CV events: antiox , pl

HPS [ ] CAD, PAD,DM, and H NVit E/C,

beta-carotene

mg,mg,mg

POComposite

endpoint (CVdeath, and MI)

y CV death: antiox , pl ; MI:antiox , pl ; CV events:

antiox , pl

HOPE [ ]

CV disease orDM +

additional CVRF

Vit E IU PO


stroke)

y CV events: Vit E , pl ; CVdeath: Vit E , pl ; MI: Vit E

, pl


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: Continued.

Source Numbero patientsInclusioncriteria

Antioxidantagent Dose Route Endpoints Followup Events

Mark et al.[ ]

Esophagealdysplasia

Vit E/C,beta-carotene

IU,mg,

and

mg

PO CV death y CV death: antiox , pl

CARE[ ]

Exposure toasbestos or

smokeVit E/A / mg,IU PO

Lung cancerincidence . y CV death: HR . ( . . )

WAVE [ ] Postmenopausal

women withCAD

Vit E/C IU,mg PO Change in

MLD . y CV events: antiox , pl ; CV

death: antiox , pl ; non atal MI:antiox , pl

HOPE [ ]

CV disease orDM +

additional CVRF

Vit E IU PO

Compositeendpoint (CV

death, MI,stroke)


, pl

CAD: coronary artery disease; CV: cardiovascular; d: days; DM: diabetes mellitus; HR: hazard ratio; H N: arterial hypertension; m: months; MI: myocardialin arction; MLD: minimal luminal diameter; na: not available; PAD: peripheral artery disease, pl: placebo; PO: per os; pts:patients; RF: risk actor; vit: vitamin;y: years.

administration o antioxidants to patients with known car-diovascular disease or with a very high-risk pro le proved tobe bene cial in a nontrivial number o studies.

6. Conclusions

Evidence supports on a molecular ground the oxidativehypothesiso atherosclerosis. Te translation o experimentalevidence in humans with studies aimed at the demonstrationo the association o oxidative stress with cardiovascularevents proved to be difficult and resulted in contrasting

ndings, particularly with administration o antioxidanttherapy. However, the selection o patients either at higherrisk or with cardiovascular disease provided much rewardingoutcomes with numerous positive studies. It seems there orethat although this theory still needs urther proo s to bede nitely clari ed, data available so ar strengthen the pivotalrole or oxidative stress in atherosclerosis.

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The Role of OxLDL in Atherosclerosis

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