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; firstname.lastname@example.orgReceived 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 modication 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 prolierating actions on monocytes/macrophages, inciting their transormation into oam cells; (b) through stimulation o smooth muscle cells (SMCs) recruitment and prolieration in the tunica intima; (c) through eliciting endothelial cells, SMCs, andmacrophagesapoptosiswithensuingnecroticcoredevelopment.Moreover,mostotheexperimentaldataonatherosclerosis-proneanimals beneting 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 benets inhealthypopulations,suggestabenetinhigh-riskpatients.Inconclusion,availabledataseemtovalidatetheoxidativemodicationhypothesis o atherosclerosis, although additional proos are still needed.
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 specic segments o the arterial tree,mainly branching points and biurcations, 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 modies the composition o the suben-dothelialextracellularmatrix.Hence,theentryolow-density lipoprotein (LDL) particles in the arterial wall ollowed by their retention through the binding o apolipoprotein Bto 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 [–], 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 ormoam cells , the hallmark o the atherosclerotic lesion.Furthermore, macrophages play a key role in atherogenesis