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Archakova et al. Vessel Plus 2018;2:34 I http://dx.doi.org/10.20517/2574-1209.2018.52 Page 3 of 10

MULTIPLE MODIFICATION OF LDL IN BLOOD PLASMA
Modification of LDL occurs due to glycation, desialylation and oxidation of lipid and protein components of
LDL, which, as shown in the studies, can eventually lead to their aggregation and the formation of immune
complexes (IC). As a result, LDL become atherogenic, which increases their capture by macrophages and
subsequent development of atherosclerosis. It was shown that modified LDL (m-LDL) are characterized
[18]
by numerous changes in carbohydrate, protein and lipid constituents . m-LDL, which were isolated from
the blood of patients with IHD, are able to accumulate cholesterol and are atherogenic. It is indicated that
m-LDL undergo changes in a particle of lipoprotein, undergo desialylation, increase electronegative charge
[19]
and become smaller and denser . Desialylated LDL stimulate intracellular esterification of free cholesterol,
which leads to the accumulation of cholesterol esters (cholesterol). When studying a number of chemical and
physical parameters, a reliable inverse correlation was found between the atherogenic LDL and the content
of sialic acid in them.

M-LDL are: cytotoxic for endothelial cells, chemotoxic for monocytes, inhibit the migration of macrophages;
induce endothelial expression of macrophage colony-stimulating factor, which is the main regulator of
macrophage survival, proliferation and differentiation; increase the synthesis of collagen in smooth muscle
cells; inhibit lipopolysaccharide-induced expression of nuclear factor-kappaB; induce apoptosis; inhibit the
release and/or functions of nitric oxide (vasospasm); increase the expression of adhesion molecules on blood
vessels; increase the tissue factor activity in endothelial cells (which leads to thrombosis); cause the synthesis
of a wide range of pro-inflammatory cytokines in macrophages; and cause an increase in circulating levels
[20]
of antibodies . Multiple modification of lipoprotein particles involves the formation of antigens against
[21]
which antibodies can be formed . It has been shown that in the blood of most patients with coronary
[22]
atherosclerosis there are circulating IC, consisting of LDL and anti-LDL antibodies . An increase in
the level of m-LDL and a high titer of antibodies to them in patients with diabetes with an existing
[23]
cardiovascular pathology was revealed in comparison with the control group .

Diabetes is a proven risk factor for developing atherosclerosis. Atherosclerotic vascular wall lesions progress
in diabetes. Numerous data indicate that blood of type 2 diabetes mellitus (DM) patients contains m-LDL
that undergo glycation. It provides non-enzymatic oxidation of LDL. It has been established that m-LDL in
the blood of patients with diabetes induce intracellular accumulation of cholesterol, which is associated with
[21]
a different modification, both with desialylation and non-enzymatic glycation .
[24]
Lankin et al. estimated the effect of the carbonyl modification of LDL on the properties of particles that
determine their increased atherogenicity, such as the formation of intermolecular crosslinks in ApoB100,
the oxidability of LDL particles and their ability for subsequent aggregation. With concomitant diabetes,
a sharp progression of atherosclerotic vascular lesions was noted. In addition, it has been shown that the
level of lipohydroperoxides in plasma LDL in patients with diabetes is 3 times higher than in patients with
ischemic heart disease; it has also been demonstrated that desialylation is observed in the serum of patients
with diabetes.

[25]
Borodachev et al. showed that in diabetic patients, the content of low-density lipoprotein
cholesterolincreases, which produces a direct atherogenic effect, while m-LDL have a small size, a greater
density than the native ones, and carry an electronegative charge, i.e., become desialylated (have a reduced
content of sialic acid) and glycated.

[26]
Bucala et al. showed a significant increase in the level of the end products of glucose oxidation and the
formation of m-LDL in the blood of patients with diabetes and CKD compared with a healthy control group.