Atherosclerosis and LipidPeroxidation

About one half of all deaths in theWesternWorld arecaused by cardiovascular disease. In contrast, atherosclero-sis is rare in countries where people suffer from starvation,indicating a strong influence ofWestern nutrition on athero-genesis. On the other hand, atherosclerosis was found to beclosely connected with oxidation of low density lipoprotein(LDL) which transports cholesterol to cells. The crucialproblem how atherosclerosis, oxidation of LDL and anoversupply of fatty food might be connected unified expertsin the fields of medicine, biochemistry, chemistry, and foodchemistry from Europe and the United States at a meetingon “Atherosclerosis and Lipid Peroxidation” held betweenApril 8 and 10, 2005, at Hortobagy near Debrecen, in theheart of the Hungarian Puszta. The meeting was sponsoredby the Hertie Foundation, embedded in the Herderexchange program between scientists of Western and East-ern Europe, and also by the Research Center for MolecularMedicine of the University of Debrecen, Medical andHealth Science Center, recognized by the European Unionas a Center of Excellence.

The first paper is presented by Daniel Steinberg (Universityof California, La Jolla, USA). He reviews the developmentof research in atherosclerosis over the past fifty years, froma medical and biochemical viewpoint. The investigation offamiliar hypercholesterolemia is a crucial milestone in theelucidation of the role of low density lipoproteins (LDL) inplaque formation. Emphasizing the strong relation ofinflammatory events to atherogenesis characterized by thepenetration of monocytes and T-cells into the developinglesions, Daniel Steinberg describes the induced activationof cytokine production and growth factors and requestswhich compounds are responsible for these alterations.

According to this author all these effects are induced by oxi-dation of lipids in LDL.

His conclusion that atherosclerosis is induced by lipid oxi-dation is supported by Gerhard Spiteller (University ofBayreuth, Germany). He reviews chemical changes inducedby atherogenesis, deducing that the most oxygen-sensitivecompounds in LDL are polyunsaturated fatty acids(PUFAs). PUFAs easily undergo lipidperoxidation (LPO) inLDL and Gerhard Spiteller emphasizes the great differencebetween the reactivity of lipidhydroperoxide moleculesgenerated in enzymatic reactions and the reactivity of per-oxyl radicals produced in non enzymatic LPO reactions.This raises the question whether LPOmight be a conse-quence of cell membrane alterations caused by injury.Indeed, it may be that it is not free cholesterol but directincorporation of nutritionally derived peroxidized choles-terol PUFA esters which causes atherogenesis. The questionis raised whether the protective properties of a fish diet arecaused by n-3-PUFAs and it is suggested that these protec-tive properties are based on the presence of furan fatty acidswhich are radical scavengers.

Hartmut K�hn et al. (Charit� Berlin, Germany) give anoverview of the expanding group of lipoxygenases. In theirmechanism of action, the lipidhydroperoxide moleculesformed are subjected to cleavage by formation of alkoxylradicals, which requires the presence of iron ions. The ques-tion how these iron ions are generated in biological samplesis outlined by Jozsef Balla (University of Debrecen, Hun-gary): because they are highly reactive, iron ions are extre-mely well shielded by complexation in biological mole-cules. In this paper the processes are outlined in detailwhich might contribute to the liberation of iron ions fromhem and the protecting properties of ferritin and hem-oxy-genase-1 are discussed.

989Mol. Nutr. Food Res. 2005, 49, 989–991 Editorial: L. Nagy and G. Spiteller

Editorial

Gerhard Spiteller (left) andL�szl� Nagy (right)

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Mol. Nutr. Food Res. 2004, 48, 989–991 Editorial: L. Nagy and G. Spiteller

The main toxic products generated in nonenzymatic lipidLPO reactions are 2,4-unsaturated aldehydic compounds.The representative of this class of compounds which hasbeen most widely investigated is 4-hydroxynonenal. Per-oxyl radicals generate a second class of toxic products, oxi-dized cholesterol derivatives. Giuseppe Poli (University ofTurin, Italy) provides an overview of the generation of bothclasses of toxic products, leading to an overexpression ofthe proteins TGFb1, MCP-1, CD36 and b1-integrin. More-over, he discusses the toxic actions of unsaturated aldehydesand cholesterol oxidation products.

In the course of nonenzymatic LPO processes, not only freePUFAs are attacked but also those bound to phospholipidsand are cleaved to aldehydic products still connected totheir glycerol skeleton. Robert Salomon et al. (CaseWes-tern University, Cleveland, USA) reports on the furtherdegradation of such aldehydes to isolevuglandins. Thesetruncated phospholipids have turned out to be importantsignalling molecules serving as ligands to proteins whichinduce an appropriate gene response. He emphasizes thatalthough the cholesterol level is reduced by therapeuticinventions, the level of the isolevuglandin protein adductincreases, thus indicating that cholesterol levels do notreflect the oxidative state of a patient.

Norbert Leitinger (University of Virginia, Charlottsville,USA) continues the discussion about the action of aldehy-dic phospholipid derivatives on tissue samples in modelstudies. He recognizes that these compounds induce expres-sion of atherosclerosis inducing genes, such as EGR-1,VCAM-1, ICAM-1, TF, and IL-6, thus contributing to vas-cular inflammation processes.

Macrophage gene expression and metabolism are regulatedby a group of lipid-activated transcription factors: PPARc(peroxisome proliferator activated receptor-gamma), LXR,liver X receptor and RAR (retinoic acid receptor). The roleof retinoids in connecting PPARc and LXR signaling inmacrophages is the main topic discussed by L�szl� Nagyet al. (University of Debrecen, Hungary). Retinoids via theretinoic acid receptor (RAR) and PPARc regulate the P450enzyme CYP27, which in turn leads to an increased level of

27-hydroxysterol (a ligand of LXR) and contributes to theregulation of lipid metabolism and cholesterol efflux inmacrophages.

The contribution by Ilona Staprans (University of Califor-nia, San Francisco, USA) deals with the uptake of food-derived oxidized cholesterol and oxidized fatty acids in cir-culating lipoproteins. She was able to demonstrate in feed-ing experiments that toxic 5,6-epoxycholesterol is incorpo-rated into lipoproteins, and points out that oxidized choles-terol derivatives are abundant in fast food, mentioning thatthese may also contribute to atherosclerosis.

The aspect of removal of radicals in tissue by scavengers isdiscussed by Regina Brigelius-Floh� et al. (University ofPotsdam, Germany). She demonstrates that antioxidants actnot only as scavenger molecules but also show pro-oxidantproperties. Furthermore, vitamin E, for instance, has alsogene-regulatory functions which have previously not beensufficiently considered. She further shows that plant consti-tuents are able to transform SH groups to redox sensitivetranscription factors which are probably more influentialthan their antioxidant potential.

This Issue provides convincing evidence that lipid peroxi-dation processes are an essential response of organisms toinjury. The products formed serve apparently as ligands toproteins which in turn induce an appropriate gene response.Therefore fatty acids seem not only to be of importance fornutrition but also for signalling purposes.

991

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L�szl� NagyUniversity of Debrecen, Hungary

Gerhard SpitellerUniversity of Bayreuth, Germany