Abstract
Oxidation of low density lipoprotein (LDL) in the artery wall leads to the formation of cholesterol oxidation products that may result in cytotoxicity. Different mechanisms could contribute to LDL oxidation in vivo resulting in characteristic and specific modification of the cholesterol molecule. Alternatively, attack on cholesterol by chain propagating peroxyl radicals could result in the same distribution of oxidation products irrespective of the initial pro-oxidant mechanism. To distinguish between these possibilities we have monitored the formation of nine oxysterols during LDL oxidation, promoted by copper, myoglobin, peroxynitrite, or azo bis amidino propane. Regardless of the oxidant used, the pattern of oxysterol formation was essentially the same. The yields of products identified decreased in the order 7-oxocholesterol > 7 beta-hydroxycholesterol > 7 alpha-hydroxycholesterol > 5,6 beta-epoxycholesterol > 5,6 alpha-epoxycholesterol except in the case of peroxynitrite in which case a higher yield of 5, 6 beta-epoxycholesterol relative to 7-oxocholesterol was found. No formation of cholestane 3 beta, 5 alpha, 6 beta-triol, or the 24-,25-,27-hydroxycholesterols was seen. Concentration of 7-oxocholesterol levels in LDL was positively correlated with the degree of protein modification. Endogenous alpha-tocopherol in LDL or supplementation with butylated hydroxytoluene prevented oxysterol formation. Taken together these data indicate that the oxidation of cholesterol and protein in LDL occur as secondary oxidation events consequent on the attack of fatty acid peroxyl/alkoxyl radicals on the 7-position of cholesterol, and with amino acids on apoB. Furthermore, oxidant processes with atherogenic potential, such as peroxynitrite, copper, and myoglobin are capable of producing oxidized LDL containing cytotoxic mediators.
Highlights
Oxidation of low density lipoprotein (LDL) in the artery wall leads to the formation of cholesterol oxidation products that may result in cytotoxicity
This results in high levels of lipid deposits within macrophages endowing them with a foamy appearance, a characteristic feature of atherosclerotic lesions [1].other mechanisms have been suggested through which oxidized LDL may contribute to the pathogenesis of atherosclerosis
The cytotoxic fraction of oxidized LDL has been identified as the specific cholesterol oxidation products, 7@hydroperoxycholesterol,7-oxocholesterol, and 7@hydroxycholesterol.These have been detected in atherosclerotic tissue [14, 16].Apart from the possibility of their formation by oxidation in vivo, they can be present in the diet [17] and an epidemiological study has suggested that the relatively high concentration of oxysterols in the diet of certain Indian immigrant populations in Britain was the cause of the abnormally high incidence of atherosclerosis in such communities [18]
Summary
AAPH was obtained from Polysciences, Warrington, PA. Horse heart myoglobin and superoxide dismutase were obtained from Sigma and SIN-1 was a generous gift from Casella A.G. 01 (cholesterol-5~,6~-epoxidec),holestane-3P,5a,6P- oxidize LDL via its decomposition to form nitric oxide triol, cholest-5-ene-3P,24-diol (24hydroxycholesterol), and superoxide [23] and AAPH decays to yield amphicholest-5ene-3P,25-diol (25-hydroxycholesterol), and pathic peroxyl radicals [35] Both SIN-1and AAPH r e p cholest-5-ene-3P,27-diol (27-hydroxycholesterol) were resent mechanisms of peroxidation in which initiation measured by a method based on isotope dilution-mass occurs independent of the presence of lipid peroxides. 90% conversion of the cholesterol peroxide to the cor- the absolute concentrations of oxysterols varied, preresponding 7a-hydroxy and 7 - 0 ~ 0analogs with little sumably due to the well-established differences in the formation of the 7kisomer This result shows that the intrinsic oxidizabilityof LDL isolated from different doanalytic method can be used for determination ofunes- nors [36].
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