Nonenzymatic lipid peroxidation

The expression of 15-LOX in atherosclerotic lesions is one of the major causes of LDL oxidative modification during atherosclerosis. To obtain the experimental evidence of a principal role of 15-LOX in atherosclerosis under in vivo conditions, Kuhn et al. [67] studied the structure of oxidized LDL isolated from the aorta of rabbits fed with a cholesterol-rich diet. It was found that specific LOX products were present in early atherosclerotic lesions. On the later stages of atherosclerosis the content of these products diminished while the amount of products originating from nonenzymatic lipid peroxidation increased. It was concluded that arachidonate 15-LOX is of pathophysiological importance at the early stages of atherosclerosis. Folcik et al. [68] demonstrated that 15-LOX contributed to the oxidation of LDL in human atherosclerotic plaques because they observed an increase in the stereospecificity of oxidation in oxidized products. Arachidonate 15-LOX is apparently more active in young human lesions and therefore, may be of pathophysiological importance for earlier atherosclerosis. In advanced human plaques nonenzymatic lipid peroxidation products prevailed [69],... 

Similar to lipids the oxidation of proteins has already been studied for more than 20 years. Before discussing the data on protein oxidation, it should be mentioned that many associated questions were already considered in previous chapters. For example, the oxidation of lipoproteins, which is closely connected with the problems of nonenzymatic lipid peroxidation was discussed in Chapter 25. Many questions on the interaction of superoxide and nitric oxide with enzymes including the inhibition of enzymatic activities of prooxidant and antioxidant enzymes are considered in Chapters 22 and 30. Therefore, the findings reported in those chapters should be taken into account for considering the data presented in this chapter. 

Cystic fibrosis is the most common lethal autosomal-recessive disease, in which oxidative stress takes place at the airway surface [274]. This disease is characterized by chronic infection and inflammation. Enhanced free radical formation in cystic fibrosis has been shown as early as 1989 [275] and was confirmed in many following studies (see references in Ref. [274]). Contemporary studies also confirm the importance of oxidative stress in the development of cystic fibrosis. Ciabattoni et al. [276] demonstrated the enhanced in vivo lipid peroxidation and platelet activation in this disease. These authors found that urinary excretion of the products of nonenzymatic lipid peroxidation PGF2 and TXB2 was significantly higher in cystic fibrotic patients than in control subjects. It is of importance that vitamin E supplementation resulted in the reduction of the levels of these products of peroxidation. Exhaled ethane, a noninvasive marker of oxidative stress, has also been shown to increase in cystic fibrosis patients [277]. 

Oxysterols are defined as oxygenated derivatives of cholest-5-en-3(3-ol (cholesterol) (Figure 18.1) or precursors of CHOL that may be formed directly by autoxidation or by the action of a specific monooxygenase, or that may be secondary to enzymatic or nonenzymatic lipid peroxidation (Guardiola et al., 1996 Schroepfer, 2000 Bjorkhem and Diczfalusy, 2002). These OS may be formed in the human body by endogenous free-radical attack on CHOL or by enzymatic processes, mainly in the biosynthesis of bile acids and steroid hormones. In addition, OS may be formed exogenously by autoxidation of CHOL in foods. The nomenclature and abbreviations of OS are presented in Table 18.1. It should be emphasized at this point that the OS that occur in... 

The discovery of the IsoPs as products of nonenzymatic lipid peroxidation has been a major breakthrough in the field of free radical research. The quantification of these molecules has opened up new areas of investigation regarding the role of free... 

HODEs are primarily Cl8 oxidation products of linoleic acid (J9). These have not been as widely studied as isoprostanes, but like isoprostanes, these are specific products of nonenzymatic lipid peroxidation that are associated with arteriosclerotic disease and are found in arteriosclerotic plaques (J9, W2). Likewise, they are measured by specific GC/MS techniques that are generally not available in clinical laboratories (JIO). They have the advantage that they are products of the major PUFA in lipoproteins—linoleic acid— but they have generally been measured only in lipoproteins extracted from plasma. 

Malondialdehyde (MDA) and 4-hydroxy-2-nonenal (HNE) are among many reactive aldehydes that are nonenzymatic lipid peroxidation products. These products are illustrated in Fig. 5. Both have been intensively studied as an index of peroxidation (E4). They are not only associated with arteriosclerosis (J9), but are among those electrophilic aldehydes that adduct lysine residues in apo B, leading to uncontrolled OxLDL uptake by macrophages (Ul). Moreover, both react with lipid hydroperoxides and decompose them to peroxyl and alkoxyl radicals, which can reinitiate lipid peroxidation (E4, J4, R5, Ul, W9). 

Enhanced production of vasoconstrictor factors via eicosanoid and/or free radical-related mechanisms has been observed in several cardiovascular disease states. In addition to the well-established role of free radicals in promoting the oxidation of low density lipoprotein cholesterol (LDL-C), changes in free radical status may modify endogenous eicosanoid profiles and/or produce nonenzymatic lipid peroxidation products of the arachidonic acid (AA) cascade such as lipid hydroperoxides and isoprostanes, which have been shown to possess potent vasoactive properties (3). Furthermore, an excess of free radicals may interact with the vascular endothelial cell nitric oxide (NO) to produce highly reactive peroxynitrite radicals, resulting in tissue damage and vasoconstriction (4—6) (Fig. 2). 

Lipooxygenase is important in early human atherosclerosis, whereas in advanced lesions the enzyme is silent and its products, that were accumulated earlier, may be decomposed or superimposed by large amounts of nonenzymatic lipid peroxidation products (375). There is an important in vivo role of vascular 12/15 lipooxygenase in VSMC growth, migration, and matrix responses associated with atherosclerosis (376). 

Sattler, S. E., L. M. Saffrane, E. E. Farmer, M. Krischke, M. J. Mueller, and D. Dellapenna. 2006. Nonenzymatic lipid peroxidation reprograms gene expression and activates defense markers in arabidopsis tocopherol-defficient mutants. Plant Cell 18 3706-3720. 

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