Low‐density lipoprotein is oxidized by phospholipase A₂ and lipoxygenase in xanthoma lesions

Abstract

Oxidized LDL has been obtained by incubation with copper ions (Cu‐LDL) or various kinds of cells. LDL incubated with xanthoma tissues (x‐LDL) is considered a model of in vivo oxidized LDL that has extravasated into xanthoma lesions. To investigate the mechanism of x‐LDL formation, we studied the effects of various enzyme inhibitors or antioxidants on the oxidation process of LDL. Thiobarbituric acid‐reactive substance (TBARS) levels, electrophoretic mobility and spectrophotometric pattern of the oxidized LDL were examined. Antioxidants suppressed TBARS formation in both x‐LDL and Cu‐LDL. Enzyme inhibitors inhibited TBARS levels in x‐LDL, but not in Cu‐LDL. All the enzyme inhibitors and antioxidants, except for the cyclooxygenase inhibitor, inhibited the anodic electrophoretic mobility of x‐LDL. The anodic electrophoretic mobility of Cu‐LDL was suppressed only with antioxidants. Spectrophotometry indicated that an increase in the absorbance at 240 nm was observed in Cu‐LDL, but not in x‐LDL. x‐LDL oxidation is primarily catalyzed by phospholipase A2, and subsequently generated polyunsaturated free fatty acids propagate the peroxidation. Fatty acid hydroperoxides conjugated with dienes are not synthesized in x‐LDL. On the other hand, non‐enzymatic oxidants, such as superoxide anion and hydroxyl radicals generate Cu‐LDL with diene‐conjugated fatty acid hydroperoxides.

Pathophysiology of Atherosclerosis

“…LDLs can be oxidized by free radicals present in the extracellular media, such as superoxide (O 2 •– ), hydroxyl radicals ( • OH) [ 90 ], and others, such as HClO, produced by the surrounding cells [ 91 , 92 ]. Additionally, LDLs can be directly oxidized by the enzymatic activity of phospholipases and lipoxygenases [ 93 , 94 ]. In fact, the lipoxygenase pathway has been highlighted to explain the initiation of LDL oxidation [ 95 ].…”