doi: 10.1161/CIRCRESAHA.107.162487
© 2007 American Heart Association, Inc.
Editorials |
Inflammation and Atherosclerosis
From Molekulare Innere Medizin, Departement für Innere Medizin, Universitätsspital Zürich, Switzerland.
Correspondence to Matthias Barton, MD, Medizinische Poliklinik, Departement für Innere Medizin, Universitätsspital Zürich, Rämistrasse 100, CH-8091 Zürich, Switzerland. E-mail barton{at}usz.ch
See related article, pages 792–801
Key Words: oxidized phospholipids • inflammation • vascular smooth muscle cells • differentiation marker genes • atherosclerosis
The deleterious effects of high low-density lipoprotein (LDL) cholesterol levels on atherosclerosis has been known for almost a century,1 yet plasma cholesterol continues to be a challenge for clinicians in the treatment and prevention of cardiovascular disease.2,3 Atherogenesis involves uptake of cholesterol in the vascular wall, followed by inflammatory activation and growth of vascular smooth muscle cells.4,5 Indeed, proinflammatory mediators such as interleukins and cytokines stimulate vascular cell growth and atherogenesis (reviewed in4), whereas inhibition of inflammatory pathways attenuates cell growth and atherosclerosis.6 Therefore, we now view atherosclerosis as a vascular inflammatory process7 as was already proposed by Virchow8 and later by Anitschkow who noticed an "infiltrative character" of atherosclerotic 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 factor–stimulated proliferation 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 of phospholipids 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), results 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 translocate 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,17–20 and angiogenesis,21 all of which are promoters of atherogenesis. At high concentrations, oxidized phospholipids promote vascular smooth muscle apoptosis,22 which may influence plaque vulnerability of atherosclerotic lesions.23,24
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In the present issue of Circulation 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 specifically 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 heavy chain), which these investigators found to be dependent on Krüppel-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 phospholipids 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 cholesterol contains high concentration of oxidized phospholipids, reminding us that lowering of plasma cholesterol will consequently 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 or the generation of oxidized phospholipids will reduce clinical manifestations of atherosclerosis. Understanding and communicating 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 particularly in children.28,29
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Acknowledgments |
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Sources of Funding
Original work of the authors is supported by the Swiss National Foundation and the University of Zürich.
Disclosures
None.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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 Top References |
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1. Anitschkow N. Über die Veränderungen der Kaninchenaorta bei experimenteller Cholesterinsteatose. Beitr Pathol Anat. 1913; 56: 379–404.
2. Libby P. The forgotten majority: unfinished business in cardiovascular risk reduction. J Am Coll Cardiol. 2005; 46: 1225–1228.
3. O’Keefe JH Jr, Cordain L, Harris WH, Moe RM, Vogel R. Optimal low-density lipoprotein is 50 to 70 mg/dl: lower is better and physiologically normal. J Am Coll Cardiol. 2004; 43: 2142–2146.
4. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005; 352: 1685–1695.
5. Hansson GK, Libby P. The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol. 2006; 6: 508–519.[CrossRef][Medline] [Order article via Infotrieve]
6. Mach F. Statins as immunomodulatory agents. Circulation. 2004; 109: II15–II17.[Medline] [Order article via Infotrieve]
7. Ross R. Atherosclerosis–an inflammatory disease. N Engl J Med. 1999; 340: 115–126.
8. Virchow R. Der atheromatöse Prozess der Arterien. Wien Med Wochenschr. 1856; 6: 809–812, 825–827.
9. Anitschkow. Experimental arteriosclerosis in animals, in Cowdry EV (ed). Arteriosclerosis: A Survey of the Problem. New York, Macmillan. 1933: 271–322.
10. Owens GK. Regulation of differentiation of vascular smooth muscle cells. Physiol Rev. 1995; 75: 487–517.
11. Libby P, Miao P, Ordovas JM, Schaefer EJ. Lipoproteins increase growth of mitogen-stimulated arterial smooth muscle cells. J Cell Physiol. 1985; 124: 1–8.[CrossRef][Medline] [Order article via Infotrieve]
12. Locher R, Brandes RP, Vetter W, Barton M. Native LDL induces proliferation of human vascular smooth muscle cells via redox-mediated activation of ERK 1/2 mitogen-activated protein kinases. Hypertension. 2002; 39: 645–650.
13. Berliner JA, Watson AD. A role for oxidized phospholipids in atherosclerosis. N Engl J Med. 2005; 353: 9–11.
14. Fruhwirth GO, Loidl A, Hermetter A. Oxidized phospholipids: from molecular properties to disease. Biochim Biophys Acta. 2007; 1772: 718–736.[Medline] [Order article via Infotrieve]
15. Bochkov VN. Inflammatory profile of oxidized phospholipids. Thromb Haemost. 2007; 97: 348–354.[Medline] [Order article via Infotrieve]
16. Moumtzi A, Trenker M, Flicker K, Zenzmaier E, Saf R, Hermetter A. Import and fate of fluorescent analogs of oxidized phospholipids in vascular smooth muscle cells. J Lipid Res. 2007; 48: 565–582.
17. Cole AL, Subbanagounder G, Mukhopadhyay S, Berliner JA, Vora DK. Oxidized phospholipid-induced endothelial cell/monocyte interaction is mediated by a cAMP-dependent R-Ras/PI3-kinase pathway. Arterioscler Thromb Vasc Biol. 2003; 23: 1384–1390.
18. Leitinger N, Tyner TR, Oslund L, Rizza C, Subbanagounder G, Lee H, Shih PT, Mackman N, Tigyi G, Territo MC, Berliner JA, Vora DK. Structurally similar oxidized phospholipids differentially regulate endothelial binding of monocytes and neutrophils. Proc Natl Acad Sci U S A. 1999; 96: 12010–12015.
19. Loidl A, Sevcsik E, Riesenhuber G, Deigner HP, Hermetter A. Oxidized phospholipids in minimally modified low density lipoprotein induce apoptotic signaling via activation of acid sphingomyelinase in arterial smooth muscle cells. J Biol Chem. 2003; 278: 32921–32928.
20. Shih PT, Elices MJ, Fang ZT, Ugarova TP, Strahl D, Territo MC, Frank JS, Kovach NL, Cabanas C, Berliner JA, Vora DK. Minimally modified low-density lipoprotein induces monocyte adhesion to endothelial connecting segment-1 by activating beta1 integrin. J Clin Invest. 1999; 103: 613–625.[Medline] [Order article via Infotrieve]
21. Bochkov VN, Philippova M, Oskolkova O, Kadl A, Furnkranz A, Karabeg E, Afonyushkin T, Gruber F, Breuss J, Minchenko A, Mechtcheriakova D, Hohensinner P, Rychli K, Wojta J, Resink T, Erne P, Binder BR, Leitinger N. Oxidized phospholipids stimulate angiogenesis via autocrine mechanisms, implicating a novel role for lipid oxidation in the evolution of atherosclerotic lesions. Circ Res. 2006; 99: 900–908.
22. Fruhwirth GO, Moumtzi A, Loidl A, Ingolic E, Hermetter A. The oxidized phospholipids POVPC and PGPC inhibit growth and induce apoptosis in vascular smooth muscle cells. Biochim Biophys Acta. 2006; 1761: 1060–1069.[Medline] [Order article via Infotrieve]
23. Clarke MC, Figg N, Maguire JJ, Davenport AP, Goddard M, Littlewood TD, Bennett MR. Apoptosis of vascular smooth muscle cells induces features of plaque vulnerability in atherosclerosis. Nat Med. 2006; 12: 1075–1080.[CrossRef][Medline] [Order article via Infotrieve]
24. Han DK, Haudenschild CC, Hong MK, Tinkle BT, Leon MB, Liau G. Evidence for apoptosis in human atherogenesis and in a rat vascular injury model. Am J Pathol. 1995; 147: 267–277.[Abstract]
25. Pidkovka NA, Cherepanova OA, Yoshida T, Alexander MR, Deaton RA, Thomas JA, Leitinger N, Owens GK. Oxidized phospholipids induce phenotypic switching of vascular smooth muscle cells in vivo and in vitro. Circ Res. 2007; 101: 792–801.
26. Liu Y, Sinha S, McDonald OG, Shang Y, Hoofnagle MH, Owens GK. Kruppel-like factor 4 abrogates myocardin-induced activation of smooth muscle gene expression. J Biol Chem. 2005; 280: 9719–9727.
27. Pipes GC, Creemers EE, Olson EN. The myocardin family of transcriptional coactivators: versatile regulators of cell growth, migration, and myogenesis. Genes Dev. 2006; 20: 1545–1556.
28. McGill HC Jr, McMahan CA, Herderick EE, Zieske AW, Malcom GT, Tracy RE, Strong JP. Obesity accelerates the progression of coronary atherosclerosis in young men. Circulation. 2002; 105: 2712–2718.
29. Napoli C, Glass CK, Witztum JL, Deutsch R, D’Armiento FP, Palinski W. Influence of maternal hypercholesterolaemia during pregnancy on progression of early atherosclerotic lesions in childhood: Fate of Early Lesions in Children (FELIC) study. Lancet. 1999; 354: 1234–1241.[CrossRef][Medline] [Order article via Infotrieve]
Related Article:
Circ. Res. 2007 101: 792-801.
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