Lipoxygenase contributes to the oxidation of lipids in human atherosclerotic plaques.

Abstract

IntroductionOxidized LDL is present in human atherosclerotic lesions, but the mechanisms responsible for oxidation in In the last decade strong evidence has accumulated supporting the concept that oxidative processes, acting on the lipids and proteins of LDL in the vessel wall, participate in the progression of atherosclerotic disease ( 1-4). Evidence from in situ studies has demonstrated that oxidized LDL, macrophages, and 15-lipoxygenase colocalize within human atherosclerotic lesions (5). We therefore chose to determine whether 15-lipoxygenase was acting upon the available lipid substrate within the lesions to cause its oxidation in vivo.Early studies by Hamberg and Samuelsson (6) demonstrated that the oxidation of polyunsaturated fatty acids PUFAs'by soybean 15-lipoxygenase was stereospecific. Kuhn et al. (7) later developed a convenient chiral phase HPLC method and used it to analyze the PUFA oxidation products from a variety of lipoxygenase enzymes, confirming that stereospecificity was a fingerprint of lipoxygenase activity. These investigators found that mammalian lipoxygenase enzymes also specifically produce the S enantiomer at the target positions of oxidation on their PUFA substrates (7). In contrast, nonenzymatic PUFA oxidation results in products positionally the same as those catalyzed by lipoxygenases but with equal quantities of both stereoisomers (R and S) at all positions of oxidation. We have recently shown that esterified, oxidized linoleate is the major oxidized PUFA in monocyte-oxidized LDL (8). Esterified, oxidized PUFA products, predominantly from linoleate, have previously been reported to be present in lesions of atherosclerosis (9-14). Kuhn et al. (14) have analyzed the oxidized PUFA products in atherosclerotic lesions using chiral phase HPLC and have recently reported detection of stereospecific oxidation in a rabbit model of the disease. Herein we report the results of our analysis of the chirality of the oxidation products in human lesions, to determine whether PUFA oxidation is catalyzed by a lipoxygenase. The quantity of cholesteryl linoleate and its oxidation products in aortae have been shown to increase with progression of vascular disease (9,10,13,15

Catalytic consumption of nitric oxide by 12/15- lipoxygenase: Inhibition of monocyte soluble guanylate cyclase activation

“…2). The presence of specific LOX products in early atherosclerotic lesions indicates that LOX catalysis occurs in vivo, although precise control mechanisms remain to be elucidated (19)(20)(21). Herein, inclusion of the metal chelator DTPA prevents secondary nonenzymatic generation of additional lipid radicals.…”

“…15-and 12͞15-LOXs play a central role in vascular disease, because (i) 15-LOX mRNA, protein, and lipid products are found in atheroma, (ii) inhibition of 15-LOX prevents atherosclerosis in rabbits, and (iii) functional inactivation of the 12͞15-LOX gene slows down aortic lipid deposition in apo E-deficient mice, and inhibits streptozotocin-induced diabetes (19)(20)(21)(22)(23)(24)(25). Furthermore, in vivo, 12͞15-LOX expression is required for neointimal thickening in ballooninjured rat aortae (26,27).…”

Leukotriene Signaling in Atherosclerosis and Ischemia

“…As lipids are taken up into the vascular wall, they undergo oxidative modifications [10]. Several studies support a lipoxygenase-mediated oxidation of low density lipoproteins (LDL) [30,31], mainly mediated trough the 15-lipoxygenase (15-LO) pathway [32]. However, recent findings have indicated an absence of 15-LO expression within atherosclerotic lesions [33], hence questioning its role as a driver of LDL oxidation in vivo.…”

The effects of oral vitamin supplementation on cardiovascular risk factors

“…1992). Oxidation may proceed more rapidly after the introduction of seeding hydroperoxides into the LDL particle by lipoxygenase enzymes (Folcik et al 1995). Regardless of the mechanisms involved, oxidation of polyunsaturated fatty acids within LDL leads to the formation of short-chain aldehydes such as malondialdehyde and 4-hydroxynonenal, which react with key lysine residues on the apoB molecule (Steinberg et al 1989).…”