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Matthias Barton, Roberta Minotti and Elvira HaasInflammation and Atherosclerosis

Print ISSN: 0009-7330. Online ISSN: 1524-4571Copyright 2007 American Heart Association, Inc. All rights reserved.is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation Research

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Inflammation and Atherosclerosis

Matthias Barton, Roberta Minotti, Elvira Haas

The deleterious effects of high low-density lipoprotein(LDL) cholesterol levels on atherosclerosis has beenknown for almost a century,1 yet plasma cholesterol continues

to be a challenge for clinicians in the treatment and preven-

tion of cardiovascular disease.2,3 Atherogenesis involves up-

take of cholesterol in the vascular wall, followed by inflam-

matory activation and growth of vascular smooth muscle

cells.4,5 Indeed, proinflammatory mediators such as interleu-

kins and cytokines stimulate vascular cell growth and athero-

genesis (reviewed in4), whereas inhibition of inflammatory

pathways attenuates cell growth and atherosclerosis.6 There-

fore, we now view atherosclerosis as a vascular inflammatory

process

7

as was already proposed by Virchow

8

and later byAnitschkow who noticed an infiltrative character of athero-

sclerotic lesions of cholesterol-fed animals.9

Differentiation and growth of vascular smooth muscle

cells, a prerequisite of atherosclerosis progression, depends

on a fine-tuned balance between activators and inhibitors of

cell growth.10 In the 1980s, Libby and colleagues reported

that LDL cholesterol enhances growth factorstimulated pro-

liferation of vascular smooth muscle cells.11 Later, it became

clear that the growth-stimulating effects of LDL cholesterol

also involves oxidative stress dependent activation of

mitogen-activated protein kinases.12 Oxidative stress leads to

the formation of so-called oxidized phospholipids, small

molecules formed from fatty acids.13,14

This oxidation ofphospholipids such as phosphatylcholine, present in LDL and

cell membranes, is mediated by reactive oxygen species and

lipoxygenases at the sn-2 position of polyunsaturated fatty

acid residues, resulting in the formation of either complete or

truncated forms of oxidized phospholipids.14 Oxidation of

phosphorylcholine-containing lipids, namely of 1-palmitoyl-

2-arachidonoyl-sn-glycero-3-phosphorylcholine (PAPC), re-

sults in several oxidized phospholipids including

1-palmytoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine

(POVPC) and 1-palmitoyl-2-glutaroyl-sn-glycero-3-

phosphocholine (PGPC), which are known proinflammatory

molecules.15 Oxidized phospholipids, particularly POVPC,14

are present in lipoproteins from where they can directly trans-locate to the plasma membrane of vascular smooth muscle cells

(Figure).16 Of note, selected oxidized phospholipids increase

monocyte adhesion to endothelial cells,17,18 kinase activation,1720

and angiogenesis,21 all of which are promoters of athero-

genesis. At high concentrations, oxidized phospholipids

promote vascular smooth muscle apoptosis,22 which may

influence plaque vulnerability of atherosclerotic lesions.23,24

In the present issue ofCirculation Research, Pidkova and

coworkers present new and important evidence supporting a

direct proatherogenic role of oxidized phospholipids.25 These

investigators report that oxidized phospholipids, and specifi-

cally POVPC, at physiological concentrations, are crucial for

cellular differentiation and growth of vascular smooth muscle

cells in vivo and in vitro. Exposure to oxidized phospholipids

inhibited cell differentiation at the level of differentiation

marker genes (smooth muscle cell -actin, myosin heavychain), which these investigators found to be dependent on

Kruppel-like transcription factor (KLF4), a known repressor

of cellular differentiation.26 In contrast, myocardin, a serum

response cofactor and inductor of genes important for a

differentiated, nonproliferative vascular smooth muscle cell

phenotype,27 was downregulated after exposure to oxidized

phospholipids (Figure). At the same time, oxidized phospho-

lipids increased expression of proinflammatory genes and

stimulated growth and apoptosis in vascular smooth muscle

cells.25 The stimulating effects on migration and proliferation

in vascular smooth muscle cells were seen using similar

concentrations of POVPC present in atherosclerotic vessels.13

Why are these data important? First, they demonstrate novel

mechanisms by which high levels of oxidized phopholipids

accelerate vascular smooth muscle cell growth and apoptosis.

Oxidative stress represents a common feature of all known

cardiovascular risk factors and is a key mechanism leading to

formation of oxidized phospholipids.14 Moreover, LDL choles-

terol contains high concentration of oxidized phospholipids,

reminding us that lowering of plasma cholesterol will conse-

quently help to reduce oxidized phospholipids levels. Finally,

the results presented by Pidkova et al25 provide yet another piece

adding to the puzzle of how inflammatory pathways contribute

to cell growth and atherogenesis.4 It appears reasonable to

speculate that either lowering of LDL-bound concentrations orthe generation of oxidized phospholipids will reduce clinical

manifestations of atherosclerosis. Understanding and communi-

cating the importance of inflammation and oxidative stress for

the progression of atherosclerosis reminds us that control and

treatment of risk factor such as high cholesterol remains an

important goal to reduce atherosclerosis in adults and particu-

larly in children.28,29

Sources of FundingOriginal work of the authors is supported by the Swiss National

Foundation and the University of Zurich.

DisclosuresNone.

The opinions expressed in this editorial are not necessarily those of theeditors or of the American Heart Association.

From Molekulare Innere Medizin, Departement fur Innere Medizin,Universitatsspital Zurich, Switze rland.

Correspondence to Matthias Barton, MD, Medizinische Poliklinik,

Departement fur Innere Medizi n, Universitatsspital Zurich, Ramistrasse100, CH-8091 Zurich, Switzerland. E-mail barton@usz.ch

(Circ Res. 2007;101:750-751.) 2007 American Heart Association, Inc.

Circulation Research is available at http://circres.ahajournals.orgDOI: 10.1161/CIRCRESAHA.107.162487

750

See related article, pages 792801

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KEY WORDS: oxidized phospholipids inflammation vascular smooth

muscle cells differentiation marker genes atherosclerosis

Figure.Schematic representation of the vascu-lar wall and effects of oxidized phospholipidson vascular smooth muscle cells growth. Inresponse to oxidative stress oxidized phosho-lipids and particularly POVPC (red) are formedfrom phospholipids (green) and present in low-density lipoprotein. POVPC modulate vascularsmooth muscle cell phenotype modulation,migration, proliferation, and production ofproinflammatory cytokines thereby promotingatherogenesis. Insert: POVPC induces expres-sion and translocation of Kruppel-like transcrip-tion factor 4 to the nucleus causing suppres-sion of smooth muscle differentiation markergene expression and myocardin. POVPC indi-cates 1-palmytoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine; EC, endothelial cells; IEL,internal elastic lamina; LDL, low-density lipopro-tein KLF4, Kruppel-like transcription factor 4;MCP-1, monocyte chemoattractant protein-1;TNF, Tumornecrosis factor; VSMC, vascularsmooth muscle cells.

Barton et al Inflammation and Atherosclerosis 751

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