Oxidized Lipids and Atherosclerosis

Each stage of atherosclerosis involves the formation of oxidized lipids, many of which are bioactive. The lipids in lipoprotein particles and cell membranes provide the substrates for the formation of these bioactive molecules. The oxidized lipids can be a product of interactions with reactive oxygen species or reactive nitrogen species (ROS/RNS), or oxidative enzymes and lipids in the vasculature.52-54 The oxidative enzymes include: myeloperoxidase, 12/15 lipooxygenase, NADPH oxidase, NADH oxidase, cyclooxygenase, P-450 enzymes, and nitric oxide synthase. Products include oxidized phospholipids, fatty acids, and cholesterol as well as specific products of enzymatic reactions, such as prostaglandins and leukotrienes. The oxidized phospholipids include products such as hexadecyl azelaoyl phosphatidyl choline, palmitoyl epoxyisoprostane phosphatidyl choline, palmitoyl oxovalerol phosphatidyl choline, palmitolyl glutaroyl phosphatidyl choline, and palmitoyl cyclopentenone phosphatidyl choline.51 Oxidized fatty acids are derived from ara-chidonic acid and include HETE, HNE, and isoprostanes. This category also includes prostaglandins, well-known products of cyclooxygenase and leukotrienes, well-known products of lipooxygenase. Products of cholesterol oxidation include 7-hydroperoxycholesterol and 22-hydroxycholesterol.

Many of these oxidized lipids have been found in atherosclerotic lesions55-57 and cells,58,59 at all stages of atherosclerosis. In addition, apoptotic bodies in atherosclerosis and IL-1 treated cells also contain oxidized lipids.59-61

Indications that oxidized lipids, found in atherosclerosis, have bioactivity, come from several types of studies. Polymorphisms, which alter the activity of oxidative enzymes, have been associated with low amounts of atherosclerosis.62,63 Knockout mice for lipooxygenase and cyclooxygenase have shown lower levels of atherosclerosis, indicating a significant role of these enzymes in atherosclerosis.64-66 Their products, prostaglandins and leukotrienes, have well-known effects on the vascula-ture.67-69 Low amounts of atherosclerosis also are found in knockout mice for the CD 36 receptor, toll-like 2 and 4 receptors, PAF receptors, P-selectin, VCAM-1, IL-8, Fractalkine, MCP-1, and M-CSF.65 66 70-72 Oxidized, but not native, phospholi-pids bind to receptors and induce activities associated with atherosclerosis.73 Oxidized phospholipids activate endothelial cells to bind monocytes. These bioactive lipids also induce production of MCP-1 and MCF by smooth muscle and endothelial cells.60,74,75 The formation of protein adducts by oxidation products, in particular, with apolipoprotein B can alter the activity of proteins. Some oxidized lipids induce immune responses by creating new epitopes.65 Also, several oxidized lipid products are potent inflammatory mediators such as platelet activating factor (PAF), PAF-like lipids, certain oxidized phospholipids, and lysophosphoti-dylcholine (LYSO-PC).76 The induction of inflammation promotes several activities, but in particular, further oxidative damage. Oxidized lipids can modify the expression of various cytokines and transcription factors that are involved in atherosclerosis77,78 and may enhance platelet activation. In contrast, oxidized lipids also apparently signal oxidative stress and act in the induction of antioxidative and cytoprotective activities.61 Thus, the oxidized lipids have a wide range of biological activities; some related to the pathogenesis of atherosclerosis and others to the protection of the vasculature.

Some of the bioactive oxidized lipids can be removed by protective enzymes such as phospholipase A2 and paraoxonase, which cleave phospholipid hydroperoxides of various carbon lengths.79,80 This activity accounts for a portion of the protective effect of HDL. It is important to remember that there are two phospholi-pases, which may have a role in atherogenesis, the nonpancreatic type of secretory phospholipids A2 and the lipoprotein-associated PLA2. The secretory form of phospholipase A2 is relatively nonspecific, calcium-dependent, and of less current interest in the risk of coronary heart disease. The lipoprotein-associated PLA2 is under intense research as a risk factor for CVD. Other protective enzymes may include ACAT and aldose reductase. Thus, the extent of oxidized lipid exposure is dependent upon a balance between their formation and enzymes which hydrolyze these oxidized products.

Oxidized phospholipids, associated with LDL, have been linked with the risk of coronary heart disease. A study of coronary artery disease patients found an association between the ratio of oxidized phospholipid:apo B-100 and the presence of vessel stenosis, greater than 50%. Since LP(a) binds proinflammatory oxidized phospholipids and was also related to the presence of stenosis, the atherogenicity of LP(a) may be mediated by an association with oxidized lipids.81,82

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