Phospholipid oxidation

Extensive studies in vitro from many groups have confirmed that exposure of LDL to a variety of pro-oxidant systems, both cell-free and cell-mediated, results in the formation of lipid hydroperoxides and peroxidation products, fragmentation of apoprotein Bioo, hydrolysis of phospholipids, oxidation of cholesterol and cholesterylesters, formation of oxysterols, preceded by consumption of a-tocopherol and accompanied by consumption of 8-carotene, the minor carotenoids and 7-tocopherol. 

To characterize phospholipid oxidation during apoptosis, cellular phospholipids were metabolically labeled at sn-2 position with a natural unsaturated florescent fatty acid containing four conjugated double bonds, cw-parinaric acid (cw-PnA) (Kagan et al, 1998 Tyurina et al, 2001). Oxidative desttuction of any part of the conjugated double bond system of... 

We further used a quantitahve procedure to determine the amounts of externalized PS on the surface of apoptohc cells based on its availability to react with fluorescamine, a non-permeating reagent readily interacting with primary amino-groups. Subsequent separahon (by high performance thin-layer chromatography) and quantitahon of fluorescamine-modified PS permits determinahon of absolute amormts of externalized PS on the outer leaflet of plasma membrane. We were also able to determine the amounts of PnA-phospholipids oxidized during apoptosis based on their disappearance in the course of apoptosis. Thus both PS oxidahon and extemalizahon could be assessed. 

Lipid hydroperoxides and phospholipid oxidation products Lipid hydroperoxides are the major primary products of LDL oxidation. Lipid hydroperoxides (LOOH) are relatively polar, non-radical intermediates of... 

Jerlich A, Pitt AR, Schaur RJ, Spickett CM (2000) Pathways of Phospholipid Oxidation by HOC1 in Human LDL Detected by LC-MS. Free Radic Biol Med 28 673... 

Porter, N. A. and Weenan, H. (1981) High performance liquid chromatographic separation of phospholipids and phospholipid oxidation products, in Methods of Enzymology, Vol. 72, S. P. Colowick and N. O. K. Kaplan, editors, Academic Press, New York, pp. 34-40. 

Fabisiak, J.P., Tyurina, Y.Y., Tyurin, V.A., Lazo, J.S., and Kagan, V.E., 1998, Random vresus selective membrane phospholipid oxidation in apoptotis role of phosphatidylserine, Biochemistry 37 13781-13790. 

Sahai, N., Biomembrane phospholipid-oxide surface interactions Crystal chemical and thermodynamic basis, J. Colloid Interface Sci., 252, 309, 2002. 

The many nonpolar C-C and C-H bonds of vitamin E make it fat soluble, and thus it dissolves in the nonpolar interior of the cell membrane, where it is thought to inhibit the oxidation of the unsaturated fatty acid residues in the phospholipids. Oxidative damage to lipids in cells via radical mechanisms is thought to play an important role in the aging process. For this reason, many anti-aging formulas with antioxidants like vitamin E are now popular consumer products. 

The only useful commercial catalyst now used is nickel, available at a 17-25% level on a support and suspended in hardened edible oil or tallow. This preserves the activity of the nickel in a form in which it can be safely and easily handled. Catalyst can be recovered and reused but will be less active. Reaction is usually effected at temperatures between 180°C and 200°C and at a pressure of about 0.3 MPa (3 bar). The catalyst is quickly poisoned by fatty acids, soaps, phospholipids, oxidized acids, sulfur compounds, halogen compounds, carbon monoxide, oxygen, and water. As a consequence, both the oil and the hydrogen should be as pure as possible. 

The Role of Phospholipid Oxidation Products in Inflammatory and Autoimmune Diseases... 

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). 

These results show that a dyslipidemic microenvironment can directly interfere with DC responses to pathogens and skew the development of T cell-mediated immunity. It will be important to specify the molecular structures within these phospholipid oxidation products that are responsible for their effects on DC function. This will eventually allow designing low molecular substances, which mimic their immunomodulatory effects. 

Berliner, J.A. et al. Evidence for a role of phospholipid oxidation products in atherogenesis. Trends Cardiovasc. Med. 11 (2001) 142-7. 

Bochkov, V.N. et al. Protective role of phospholipid oxidation products in endotoxin-induced tissue damage. Nature 419 (2002a) 77-81. 

Subbanagounder, G. et al. Evidence that phospholipid oxidation products and/or plateletactivating factor play an important role in early atherogenesis in vitro and In vivo inhibition by WEB 2086. Circ. Res. 85 (1999) 311-8. 

Subbanagounder, G., A.D. Watson, and J.A. Berliner Bioactive products of phospholipid oxidation isolation, identification, measurement and activities. Free Radic. Biol. Med. 28... 

Walton, K.A. et al. Specific phospholipid oxidation products inhibit ligand activation of tolllike receptors 4 and 2. Arterioscler. Thromb. Vase. Biol. 23 (2003a) 1197-203. 

In this manuscript we review the recent literature reporting on apoptosis inducing glycerophospholipids. In addition, we describe the cellular processes that lead to phospholipid oxidation as part of the apoptotic mode of cell death and are likely to enhance the recognition of apoptotic cells by phagocytic macrophages. 

Lysophosphatidylcholine is a frequent product of oxidized phospholipid hydrolysis and shows structural similarities to its diacyl counterparts containing a short acyl chain in sn-2 position. Therefore, its cellular activities deserve particular attention, especially in the context of its cytotoxicity. The effects of phospholipid oxidation products and lyso-PC depend not only on their concentration but also on the cell type. Lyso-PC containing a long acyl chain in sn- position (e.g. C16 0, C18 0) is an amphiphilic phospholipid that is generated by phospholipase-catalyzed hydrolysis of phosphatidylcholine or extensive oxidation leading to loss of the entire sn-2 acyl chain. Its critical micellar concentration (CMC) is around 50 pM. It is easily taken up into lipid membranes and increases their fluidities . Above the CMC it forms micelles that destroy membrane integrity also by removal of proteins as shown in erythrocytes (Bierbaum et al., 1979 Colics and Chisholm, 2000). Lyso-PC exerts apoptotic effects in rVSMCs at concentrations below its CMC and induces necrotic cell death at concentrations above its CMC (Hsieh et al.,... 

Chen, R, Yang, L, and McIntyre, T M, Cytotoxic Phospholipid Oxidation Products Cell Death from Mitochondrial Damage and the Intrinsic Caspase Cascade, J. Biol. Chem. 282 (2007) 24842-24850. 

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