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Page 4 of 14 Orekhov et al. Vessel Plus 2019;3:3 I http://dx.doi.org/10.20517/2574-1209.2018.80

Table 1. Characteristics of naturally occurring modified low-density lipoprotein discovered in circulation of atherosclerotic
patients
Parameter sdLDL LDL(-) Desialylated LDL
Intracellular cholesterol accumulation (atherogenicity) ↑ ↑ ↑
Size ↓ ↓ ↓
Density ↑ ↑ ↑
(-) Charge ↑ ↑ ↑
Sialic acid ↓ ↓ ↓
Cholesteryl esters ↓ ↓ ↓
Phospholipids ↓ ↓ ↓
Protein/lipids ↑ ↑ ↑
Oxidizability ↑ ↑ ↑
Oxidation ↑ ↑ ↑
Antioxidants ↑ ↑ ↑
Amino group modification ? ↑ ↑
Self-association ↑ ↑ ↑
Adopted from , with permission. LDL: low-density lipoprotein; sdLDL: small dense LDL; ↑: increased; ↓: decreased; ?: not known
[9]
of LDL oxidation was detected in the blood of atherosclerotic patients [5,9,10] . Earlier, some signs of oxidation
were found in LDL isolated from the blood [5,9,10] .

The following arguments are usually made in favor of the fact that oxidized LDL plays a key role in
atherogenesis: (1) in the blood of patients, antibodies to malondialdehyde-LDL (MDA-LDL) were
discovered [5,9,10] ; (2) antibodies obtained to in vitro oxidized LDL co-localized with LDL in histological
sections of atherosclerotic lesions [5,9,10] ; and (3) LDL isolated from the artery wall possessed some
[12]
characteristic properties of oxidized LDL . However, all these arguments can be questioned. First, MDA-
LDL cannot be regarded as an adequate model of oxidized LDL. Usually, antibodies are produced against
LDL modified in vitro with MDA or copper-induced oxidation. This modification leads to random and
non-specific exposure of immunogenic sites different from those present in LDL oxidized in vivo. Second,
antibodies isolated from the blood show cross-reactivity with MDA-LDL, naturally occurring multiply
modified LDL and in vitro desialylated LDL. Anti-LDL antibodies possess the maximal affinity for
desialylated LDL; the affinity for oxidized LDL is an order of magnitude lower [5,9,10] . Thus, antibodies are
produced primarily to the desialylated LDL. Third, although oxidized LDL is not detected in the blood, other
forms of atherogenic modification (sdLDL, LDL- and desialylated LDL) are clearly detected in the circulating
lipoprotein. Multiply modified atherogenic LDL circulating in the blood of atherosclerotic patients was
detected, isolated and intensively studied [5,9,10] . The presence of sdLDL in the blood is currently known
and well-studied providing some impact on the anti-atherosclerotic therapy [5,9,10] . The results of intensive
study of LDL- have found implications in both diagnostics and therapy [5,9,10] . Despite numerous attempts of
clinical implementation of methods for determining MDA-LDL, they are still not widely used. Fourth, as
mentioned above, modification of LDL in the plasma of atherosclerotic patients begins with desialylation
followed by changes in lipid content, decrease in size and increase in density. At later stages, LDL becomes
more electronegative. Only at the very end of this cascade of transformations, the lipoprotein acquires the
properties of oxidized particle [Figure 1]. Thus, oxidation is neither the primary nor the only atherogenic
modification of LDL.

Taking into account the key role of the multiply modified atherogenic LDL in the initiation and progression
of atherosclerosis, it is reasonable to assume that atherosclerotic risks are dependent not as much on the total
content of LDL in the blood as on the level of multiply modified LDL. In this regard, the level of multiply
modified LDL should be a better biomarker of atherosclerosis than the total LDL level. Such a conclusion
will be true for HDL because dysfunctional HDL has been detected in the blood of atherosclerotic patients.

To understand which modification plays the key role conveying atherogenic properties of a lipoprotein
particle, we studied correlations between the changes in chemical and physical parameters of the multiply