5-Lipoxygenase atherosclerosis

Mechanisms of lipid peroxidation that have been implicated in atherosclerosis may be pertinent to RA. Cellular lipoxygenase enzymes may promote LDL modification by inserting hydroperoxide groups into unsaturated fetty-acid side chains of the LDL complex (Yla-Herttuala etal., 1990). 15-Lipoxygenase has been implicated as an initiator of LDL oxidation (Cathcart etal., 1991) whilst 5-lipoxygenase does not appear to be involved (Jessup et al., 1991). Products of activated lipoxygenase enzymes within inflammatory synovial fluid surest that this pathway could be activated in RA (Costello etal., 1992). 

Cathcart, M.K. and Folcik, V.A., Lipoxygenases and atherosclerosis protection versus pathogenesis, Free Radical Biol. Med., 28, 1726, 2000. 

Vila L. 2004. Cyclooxygenase and 5-lipoxygenase pathways in the vessel wall Role in atherosclerosis. Med Res Rev 24 399—424. 

Sterol carrier protein 2 has also been shown to be involved in the intracellular transport and metabolism of cholesterol. Hirai et al. (1994) suggested that sterol carrier protein 2 plays an important role during foam cell formation induced by acetylated LDL and may be an important step in atherosclerosis [142], Lipoproteins can bind lipopolysaccharide and decrease the lipopoly-saccharide-stimulated production of proinflammatory cytokines [142, 143], In addition, lipoprotein entrapment by the extracellular matrix can lead to the progressive oxidation of LDL because of the action of lipoxygenases, reactive oxygen species, peroxynitrite, or myeloperoxidase [144, 145],... 

Besides 12-LOX in platelets, the 5-LOX isoforms are constitutive in neutrophils. Evidences indicate that LOXs are involved in inflammation diseases and in atherosclerosis. 5-LOX is the enzyme that catalyzes the formation of leukotrienes with potential role for leukocytes and platelets interaction and inflammation. After platelet and leukocyte stimulation, products of both COX-1 and 5-LOX pathways increase. COX-1 activity derivatives increase the vascular permeability mediated by prostaglandins and produce platelet aggregation mediated by TXA2. The product of the lipoxygenase pathway, 5-oxo-6,8,1 1,14-eicosatetraenoic acid (5-Oxo-ETE), induces leukocyte chemotaxis and inflammation. 5-Oxo-ETE is formed by the oxidation of 5S-hydroxy-ETE (5-HETE) by 5-hydroxyeicosanoid dehydrogenase (5-HEDH), a microsomal enzyme found in leukocytes and platelets (42). 

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... 

Figure 15. Electron spin resonans signal of phenoxyl probucol radical in LDL of patients with atherosclerosis, which were treated with 250 mg probucol daily during 3 months, after oxidation of those LDL by animal (rethiculocyte) C-15 lipoxygenase and decomposition of LDL lipohydroperoxyde by hemin.

Phenolics are one of the major groups of non-essential dietary components that have been associated with the inhibition of atherosclerosis and cancer. The bioactivity of phenolics may be related to their antioxidant behavior, which is attributed to their ability to chelate metals, inhibit lipoxygenase, and scavenge free radicals. However, phenolics can also function as prooxidants by chelating metals in a manner that maintains or increases their catalytic activity (Fig. 6). Also, poly-phenolics reduce metals, thereby increasing their ability to form free radicals from peroxide. 

Arachidonic acid lipoxygenases are involved in the synthesis of biomodulators which are strictly related to various diseases allergy, inflammation, atherosclerosis and cancer [77]. 5-Lipoxygenase catalyzes the first step of reactions leading to 5-hydroxyeicosatetraenoic acid (5-HETE) and leukotriens responsible for inflammatory and allergic responses. 12-Lipoxygenase catalyzes the formation of 12-HETE, involved in atherosclerosis and tumor metastasis [76]. 

Shen J, Herderick E, Comhill JF, Zsigmond E, Kim H-S, Kuhn H, Guevara NV, Chan L Macrophage-mediated 15-lipoxygenase expression protects against atherosclerosis development. 

Dwyer, J.H. et al., Arachidonate 5-lipoxygenase promoter genotype, dietary arachi-donic acid, and atherosclerosis, N. Engl. J. Med., 350, 29, 2004. 

Mehrabian M, Allayee H, Wong J, et al.. Identification of 5-lipoxygenase as a major gene contributing to atherosclerosis susceptibility in mice, Circ Res, Jul 26 2002 91(2) 120-126. 

It should not be assumed that hydroxy fatty acids are biologically inactive. Hydroxy fatty acids are chemotactic and vasoactive. Such fatty acids could perturb phospholipids in membranes. For instance, cardiolipin containing hydroxy-linoleic acid does not support the electron transport coupled to ATP production of the mitochondrion. 5-Hydroxy de-canoic acid is a well-known inhibitor of the K -ATP channel. Isoprostanes, trihydroxy oxidation products of arachi-donic acid, are vasoconstrictors (76). 13-Hydroxy linoleic acid (13-HODE) is a lipoxygenase-derived metabolite that influences the thromboresistant properties of endothelial cells in culture (77). However, there is some doubt about the tme nature of these hydroxy-fatty acids generated by the cells, as there are several GSH- and NADPH-dependent pathways that can immediately reduce hydroperoxy- to hydroxy-fatty acids. Furthermore, the reduction step of the analytical method would have converted the hydroperoxy- to a hydroxy-group. Nevertheless, much work remains to be done to determine the relative contribution of hydroperoxy- and hydroxy- to the biological effects of fried fat, and in particular their role in endothelial dysfunction and activation of factor VII. There have been earlier suggestions that a diet rich in lipid peroxidation products may lead to atherosclerosis and CHD (34,78). 

Wittwer, J. and M. Hersberger 2007. The two faces of the 15-lipoxygenase in atherosclerosis. Pmstaslandins Leukot Essent Fatty Acids 77(2) 67-77. 

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