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Orekhov et al. Vessel Plus 2019;3:3 I http://dx.doi.org/10.20517/2574-1209.2018.80 Page 5 of 14

modified LDL and its ability to induce intracellular cholesterol accumulation. The only statistically
significant correlation was found between the atherogenic potential of LDL and sialic acid content of the
particles. This correlation was reversed: the lower was the sialic acid content of LDL, the more cholesterol
was accumulated by the cells. LDL parameters such as size, charge, lysine-free amino groups, phospholipids
and neutral lipids content, fat-soluble antioxidants, lipid peroxidation products, oxidation and oxidation
rates did not correlate significantly with LDL atherogenicity [5,9,10] . Thus, desialylation appeared to be the most
important modification inducing LDL atherogenicity. Presumably, the necessary and sufficient condition for
the appearance of atherogenic properties in LDL particles is desialylation.

Studying of the mechanisms of LDL desialylation led to the discovery of trans-sialidase activity in the blood
of atherosclerotic patients [5,9,10] . It was present both in association with lipoproteins and in free form in blood
plasma. The exact identity of the sialidase activity is not known, yet, however, LDL treated with isolated
trans-sialidase lost sialic acid and became atherogenic causing the accumulation of cholesteryl esters in
cultured cells [5,9,10] . Thus, trans-sialidase found in the blood causes LDL-lipid desialylation, which leads to
foam cells formation. Circulating trans-sialidase is a protein of about 65 kDa, whose content ranges from
20-200 µg/mL. Three optimum pH values were found: 3.0, 5.0 and 7.0. The enzyme activity was found to be
stimulated by calcium and magnesium ions and dependent on the sulfhydryl groups. Donors of sialic acid
for trans-sialidase are LDL, intermediate-density lipoprotein (IDL), very low-density lipoprotein (VLDL),
and HDL. Preferable substrate is LDL, but VLDL, IDL and the least HDL may also serve as substrate. It is
likely that trans-sialidase plays a key role in the in vivo atherogenic modification of lipoprotein particles.

LDL association
The formation of different associates containing modified LDL considerably increase lipoprotein
atherogenicity. There were found at least three ways of potentiating LDL atherogenicity: self-association of
LDL particles, LDL association with the extracellular matrix components and formation of LDL-containing
immune complexes.

Unlike native LDL, desialylated LDL particles are associated with spontaneously in vitro in cell culture
conditions [5,9,10] . A significant direct correlation was found between the atherogenicity of desialylated LDL
and the degree of lipoprotein particles’ association [5,9,10] . If the LDL associates formed in culture are removed
from the medium by filtration, this completely prevents the intracellular cholesterol accumulation. It was
shown that increased atherogenicity of desialylated LDL self-associates is a result of increased uptake of
lipoprotein particles by phagocytosis and a decrease in the rate of intracellular degradation [5,9,10] . If the self-
associates of LDL circulate in the blood of atherosclerotic patients or are formed in the arterial intima, then
self-association is the actual mechanism of increasing the atherogenic potential of desialylated LDL.

Another mechanism of enhancing atherogenicity of desialylated LDL, namely, the formation of lipoprotein
[11]
associates with the connective tissue matrix components has been found . It was reported that LDL forms
associates with collagenase-resistant arterial debris, collagen, elastin and proteoglycans isolated from human
aortic intima [5,9,10] . All these associates caused cholesterol accumulation in cultured cells. On the other hand,
LDL(-) does not induce the formation of foam cells but high susceptibility of LDL(-) to association is a factor
[13]
that favors the formation of foam cells .
Desialylation of LDL particles provokes the production of autoantibodies that form circulating immune
complexes (CIC) containing LDL. Such CIC were detected in the blood of atherosclerotic patients [5,9,10] . A
correlation was found between the levels of LDL containing immune complexes in the blood serum and the
severity of atherosclerosis in patients [5,9,10] . It was found that LDL isolated from CIC is not only desialylated,
but is also small, dense, more electronegative, and has decreased the content of neutral lipids, phospholipids
and neutral saccharides, and is also characterized by conformational changes in the tertiary apoB structure.
These findings allow considering LDL from CIC to be identical to multiply-modified LDL. LDL-containing