Oxidized phospholipids atherosclerosis

Leitinger N. (2003). Oxidized phospholipids as modulators of inflammation in atherosclerosis. Curr. Opin. Lipidol. 14 421 130. 

Leitinger, N. Oxidized phospholipids as triggers of inflammation in atherosclerosis. Mol. Nutr. Food Res. 49 (2005) 1063-71. 

Tsimikas, S. et al. Increased plasma oxidized phospholipid apolipoprotein B-lOO ratio with concomitant depletion of oxidized phospholipids from atherosclerotic lesions after dietary lipid-lowering a potential biomarker of early atherosclerosis regression. Arterioscler. Thromb. Vase. Biol. 27 (2007) 175-81. 

Tsimikas, S. et al. Oxidized phospholipids predict the presence and progression of carotid and femoral atherosclerosis and symptomatic cardiovascular disease five-year prospective results from the Bruneck study. J. Am. Coll. Cardiol. 47 (2006) 2219-28. 

Hirafuji, M., Machida, T., Hamaue, N., Minami, M. 2(X)3. Cardiovascular protective effects of n-3 polyunsaturated fatty acids with special emphasis on docosahexaenoic acid. J. Pharmacol. Sci. 92 308-316. Berliner, J.A., Watson, A.D. 2005. A role for oxidized phospholipids in atherosclerosis. N. Engl. J. Med. 353 9-11. 

Several other biological actions of oxidized lipids have also been described. Oxidized phospholipids can induce migration and proliferation of smooth muscle cells to form an atherosclerotic cap, which is a factor in the development of vascular lesions (Chatterjee et al., 2004). This corresponds to a phenotypic switching from a contractile to a de-differentiated proliferative ceU type this is now understood to represent a response to injury and can be considered in part as a protective response that attempts to repair the vessel (Spin et al., 2012). Also relevant to atherosclerosis... 

Berliner JA, Leitinger N, Tsimikas S. The role of oxidized phospholipids in atherosclerosis. The Journal of Lipid Research 2009 50 Suppl S207-12. 

Q8 In type 1 diabetes, because of a lack of insulin, a high level of triglyceride is stored in the liver and can subsequently be converted to phospholipids and cholesterol. Hepatocytes synthesize VLDLs, which can be converted to other types of lipoproteins. These lipoproteins are major sources of cholesterol and triglycerides for most other tissues. They leave the liver, enter the blood and can result in rapid development of vascular atherosclerosis. Increased levels of atherogenic oxidized low-density lipoproteins (LDLs) are seen in hyperglycaemic individuals and contribute to macrovascular disease, which is a complication of diabetes mellitus. 

We isolated the LDL fraction from plasma of patients with atherosclerosis who had been on probucol (daily dose 250 mg) for 3 months and oxidized this probucol-contained LDL by C-15 animal lipoxygenase in vitro [31]. After decomposition of enzymatically accumulated acyl-lipohydroperoxides in LDL phospholipids by hemin with corresponding... 

Abstract. The significance of free radical oxidation of phospholipids in tissues of animals with experimental atherosclerosis was investigated. By using modem physico-chemical methods an elevated content of polyunsaturated fatty acids and other lipids peroxides was discovered in the blood and the aorta of rabbits with experimental atheromatosis. The human blood demonstrated a low level of protective enzymatic systems and a high content of products secondary to peroxidal oxidation of the lipids. The mechanism accounting for the action of lipids peroxides on the vascular wall resulting in the formation of atheromatous plaques is considered. 

Abstract. When experimental animals are kept on an atherogenic diet the NADPH-dependent phospholipid deoxygenase in the membranes of the hepatic endoplasmic reticulum is activated and the degree of membrane oxidation is increased. Peroxide modification of microsomal membranes is attended by changes in their conformation and as a consequence, changes in the activity of membrane-bound enzymes. Proceeding from the fact that the synthesis of the components and the assembly of the supramolecular lipoprotein structure as well as cholesterol catabolism are accomplished by the enzyme systems localized in the hepatic microsomes, the role of peroxidation of the microsomal lipids in the pathogenesis of atherosclerosis is discussed. 

There is extensive evidence that accumulation and subsequent oxidative modification of LDL particles in the subendothelial space play a key role in development and progression of atherosclerosis (Lusis 2000 Berliner et al. 1995 Leitinger 2005). Phospholipid oxidation products are found at high concentrations within fatty streak lesions of cholesterol fed rabbits, mice, and in human atherosclerotic lesions (Watson et al. 1997 Berliner et al. 2001 Subbanagounder et al. 2000 Subbanagounder et al. 2000 Huber et al. 2002). Antibodies against OxPL are present in the serum of apoE-deficient mice and the presence of antibodies against OxPL in patients with atherosclerosis, diabetes, hypertension and other chronic inflammatory diseases further underlines the importance and potential functional relevance of these molecules (Binder et al. 2005). 

The oxidation of AA at C-15 is catalyzed by 15-LOXl, a soluble 661 amino acid-containing protein with a molecular weight of 74,673. Many cells express this enzyme that also efficiently oxidizes linoleic acid to 13-hydroperoxyoctadecadienoic acid and, to a lesser extent, 9-hydroperoxyoctadecadienoic acid because of broad substrate specificity to both 12-HpETE and 15-HpETE [31]. One distinguishing feature of 15-LOXl is that it can oxidize A A esterified to membrane phospholipids, thus forming esterified 15-HpETE. Expression of 15-LOXl is enhanced by several interleukins, suggesting a role of this enzyme in events such as atherosclerosis. 

The major bioactive products of fatty acid metabolism relevant to atherosclerosis are those that result from enzymatic or non-enzymatic oxidation of polyunsaturated long-chain fatty acids. In most cases, these fatty acids are derived from phospholipase A2-mediated hydrolysis of phospholipids (Chapter 11) in cellular membranes or lipoproteins, or from lysosomal hydrolysis of lipoproteins after internalization by lesional cells. In particular, arachidonic acid is released from cellular membrane phospholipids by arachidonic acid-selective cytosolic phospholipase Aj. In addition, there is evidence that group II secretory phospholipase Aj (Chapter 11) hydrolyzes extracellular lesional lipoproteins, and lysosomal phospholipases and cholesterol esterase release fatty acids from the phospholipids and CE of internalized lipoproteins. Indeed, Goldstein and Brown surmised that at least one aspect of the atherogenicity of LDL may lie in its ability to deliver unsaturated fatty acids, in the form of phospholipids and CE, to lesions (J.L. Goldstein and M.S. Brown, 2001). 

A relatively new class of oxidized arachidonic acid derivatives with potential relevance to atherosclerosis are F2 isoprostanes [24] (Fig. 6) (Chapter 12). These compounds form as a result of non-enzymatic, free-radical attack of the fatty acid moieties of cellular or lipoprotein phospholipids, followed by release of the isoprostanes from the phospholipids by a phospholipase. 8-wo-prostaglandin-F2 may also be formed by the action of COX-1 or -2 in platelets or monocytes, respectively, but the significance of COX-dependent 8-W0-PGF2 formation in vivo is unproven. Fj isoprostanes circulate in the plasma and appear in the urine as free compounds or esterified to phospholipids, and... 

Dietary intake of n-6 fatty acids such as linoleic acid, and n-3 fatty acids, such as the fish oils eicosapentanoic acid and docosahexaenoic acid, lowers plasma cholesterol and antagonizes platelet activation, but the fish oils are much more potent in this regard [26]. In particular, n-3 fatty acids competitively inhibit thromboxane synthesis in platelets but not prostacyclin synthesis in endothelial cells. These fatty acids have also been shown to have other potentially anti-atherogenic effects, such as inhibition of monocyte cytokine synthesis, smooth muscle cell proliferation, and monocyte adhesion to endothelial cells. While dietary intake of n-3 fatty acid-rich fish oils appears to be atheroprotective, human and animal dietary studies with the n-6 fatty acid linoleic acid have yielded conflicting results in terms of effects on both plasma lipoproteins and atherosclerosis. Indeed, excess amounts of both n-3 and n-6 fatty acids may actually promote oxidation, inflammation, and possibly atherogenesis (M. Toberek, 1998). In this context, enzymatic and non-enzymatic oxidation of linoleic acid in the sn-2 position of LDL phospholipids to 9- and 13-hydroxy derivatives is a key event in LDL oxidation (Section 6.2). 

Phospholipids comprise the outer monolayer of lesional lipoproteins and the membranes of lesional cells. In lipoproteins, the phospholipid monolayer provides an amphipathic interface between the neutral lipid core and the aqueous external environment, and provides the structural foundation for the various apolipoproteins (Chapter 18). In the specific context of atherosclerosis, the phospholipids of lesional lipoproteins are modified by various oxidative reactions that could have important pathological consequences. In lesional cells, membrane phospholipids not only play structural roles but also are precursors to important phospholipase-generated signaling molecules that may participate in atherogenesis. 

---