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The Role of OxLDL in Atherosclerosis

The Role of OxLDL in Atherosclerosis

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Published by: Alexis Jesus Gomez on Jul 18, 2014
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Hindawi Publishing CorporationMediators o In󿬂ammationVolume 󰀲󰀰󰀱󰀳, Article ID 󰀷󰀱󰀴󰀶󰀵󰀳, 󰀱󰀳 pageshttp://dx.doi.org/󰀱󰀰.󰀱󰀱󰀵󰀵/󰀲󰀰󰀱󰀳/󰀷󰀱󰀴󰀶󰀵󰀳
Review Article
The 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. Calò
Department of Medicine (DIMED), Internal Medicine 󰀴, University of Padova, Via Giustiniani 󰀲, 󰀳󰀵󰀱󰀲󰀸 Padova, Italy 
Correspondence should be addressed to Lorenzo A. Cal`o; renzcalo@unipd.itReceived 󰀱󰀰 June 󰀲󰀰󰀱󰀳; Accepted 󰀲󰀸 August 󰀲󰀰󰀱󰀳Academic Editor: Ishak ekinCopyright © 󰀲󰀰󰀱󰀳 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 inatherogenesistakingintoaccountdataderivedbystudiesbasedonmolecularandclinicalapproaches.Experimentaldatacarriedoutin 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, andmacrophagesapoptosiswithensuingnecroticcoredevelopment.Moreover,mostotheexperimentaldataonatherosclerosis-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 inhealthypopulations,suggestabene󿬁tinhigh-riskpatients.Inconclusion,availabledataseemtovalidatetheoxidativemodi󿬁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,theendotheliumexpressesadhesionandchemotacticmolecules and acquires an increased permeability to macro-molecules, which modi󿬁es the composition o the suben-dothelialextracellularmatrix.Hence,theentryo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 [󰀶]. Teretain the capability o binding to the LDL receptor [󰀶, 󰀷] and to exert their proatherogenic effects [󰀸󰀱󰀰], including stimulation o the resident vascular cells to produce mono-cyte chemotactic protein-󰀱, granulocyte, and macrophagecolony-stimulating actors. Tese molecules promote mono-cytesrecruitmentandtheirdifferentiationintomacrophages,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
 
󰀲 Mediators oIn󿬂ammation
Endothelialdysfunction
 NOS
 Permeability 
 Adhesion molecules
 ChemoattractantsHypertensionDyslipidemiaCigarette smokingDiabetesTrapping andmild oxidationMonocytesMacrophageProteoglycansLDLOxLDLScavengerreceptors
 SMCs migration
 Proliferation
 Collagen synthesis
 Inflammation
 ptls adhesion
 Lymph
++++++
PDGF
 F  G  F  
MMPs
M  C  S  F  
  M C  P -  1
IntimaSMCECT lymphocytesLipidsCell debrisLysosomal enzymesFibrous capROSApoptosisFoam cellEntry 
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-limitingeffectsoritsdestabilizationwithensuingthrombosis.Unortunately, the latter complication, which is responsibleor ischemic events, is not strictly related to the degreeo stenosis at angiography [󰀱󰀴, 󰀱󰀵] as its occurrence stands mostly 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-dizedLDLsinatherogenesistakingintoaccountdataderivedby 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 be internalizedandaccumulatedavidlybymacrophages[󰀲󰀱,󰀲󰀲], leading to oam cell ormation, although these cells couldalso be generated rom macrophages internalizing nativeLDLsromthemediumthroughmicropinocytosis[󰀲󰀳],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 plaques but not in normal vessels [󰀲󰀶] and (󰀲) its inhibition was
 
Mediators oIn󿬂ammation 󰀳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 [󰀳󰀰] and modi󿬁es LDLs, thus increasing their affinity or CD󰀳󰀶 andSR-A [󰀳󰀱, 󰀳󰀲], the scavenger receptors mediating the uptake o 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 pacetoolowtoaccountoroamcellsormation[󰀳󰀳]owingtoLDLreceptor 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-sionmolecule-󰀱andvascular-celladhesionmolecule-󰀱 [󰀳󰀶], are mitogenic or macrophages [󰀳󰀷], and promote 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) OxidizedLDLsincreasetheexpressiono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 induces SMCs prolieration [󰀴󰀲].(iii) Oxidized LDLs stimulate collagen production by SMCs[󰀴󰀳],thuscontributingtothe󿬁brouscapliningthe 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 ensuing release in the subendothelial space o lipids andlysosomal enzymes, enhancing the progression o theatherosclerotic plaque [󰀴󰀷] and the production o thenecrotic core.(v) OxidizedLDLsstimulateplateletadhesionandaggre-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 plasminogenactivator 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 modelswhereeitheramodulationooxidativestressormanipulationo the scavenger receptor was undertaken, in order to provethe role o oxidized LDLs in the pathogenesis o atheroscle-rosis.Inananimalmodeloincreasedoxidativestressobtainedthrough 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 oxidative stress, 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 not con󿬁rmed in another mice model with a CD󰀳󰀶 and SR-Adouble knockout [󰀶󰀹].Te results o these studies proved to be highly contra-dictory,duetothedifferentanimalmodelsused,thedifferentgenetic 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-proneanimalswithantioxidants(reviewed by Witztum and Steinberg [󰀷󰀱]). Most o these studies 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 F
2
 isoprostanes,a marker o oxidative stress, was observed [󰀷󰀲].

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