We Must Abandon the Myth: Oxidized Low-density Lipoprotein is not a Lipoprotein that Plays a Key Role in Atherogenesis

The purpose of this review is to revisit in detail the arguments supporting or disproving the hypothesis that oxidized low-density lipoprotein (LDL) plays a key role in atherosclerotic lesion development. The detection of oxidized LDL in vivo was extremely important for confirming its key role in atherogenesis. Indirect evidence of its existence included the presence of autoantibodies against malondialdehyde-treated LDL in human blood; however, the affinity of circulating antibodies to another LDL modification, such as desialylated LDL, was an order of magnitude stronger. At least 3 forms of atherogenic modified lipoproteins were isolated from the blood of atherosclerotic patients using different methods, namely, small dense, electronegative and desialylated. Their properties were so similar that it was suggested that the three types could be classified as the same multiple-modified LDL particle. It has been shown that when native (unmodified) LDL is incubated with autologous serum from patients with atherosclerosis, multiple modifications occur, which include desialylation, a decrease in the content of phospholipids and neutral lipids, a decrease in particle size, an increase in negative charge and other physical and chemical changes. Longer incubation also increased the susceptibility of LDL to oxidation. Thus, LDL oxidation is not the only, much less the most important, form of atherogenic modification of LDL since it occurs at the last stages of multiple modifications cascade and does not significantly increase the atherogenic potential of multiple-modified LDL. Finally, clinical trials did not support the oxidative hypothesis; however, research on oxidized LDL continues, influencing the future research. It is time to abandon the myth!