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Orekhov et al. Vessel Plus 2019;3:3 I http://dx.doi.org/10.20517/2574-1209.2018.80 Page 7 of 14
[16]
inflammatory or anti-inflammatory pathways . Oxidized LDL loading of macrophages negatively regulates
pro-inflammatory gene expression and implicates epigenetic mechanisms such as histone deacetylase
[17]
activity . On the other hand, an increase in circulating levels of IL-17 has been demonstrated in patients
with cardiovascular disease, as well as its high expression in atherosclerotic lesions, suggesting that IL-17
could affect cell targets such as macrophages in atherosclerotic lesion. In this sense, it has been shown that
[18]
IL-17 alone induces few foam cells .

FACTORS AFFECTING THE FORMATION OF FOAM CELLS
Once the ability of atherogenic modified LDL circulating in the blood of atherosclerotic patients to cause
lipid accumulation in cultured cells (atherogenicity or atherogenic potential) has been found, a natural desire
to check agents that potentially could influence the foam cell formation arose. Interest was motivated by the
fact that the detection of an agent preventing the accumulation of intracellular lipids could be considered
as the discovery of a potential anti-atherogenic drug. Hundreds of different substances were tested. Among
them, those that suppressed the accumulation of lipids in cultured cells, and those that increased the
[19]
atherogenic potential of LDL were detected; there were also such agents that had no effect .

An important part of the most recent works devoted to foam cell formation is associated precisely with the
search for modulators of intracellular lipid accumulation. Ceramide generated as a result of aggregated LDL
[20]
catabolism in atherosclerotic plaques activates macrophage RhoA . RhoA activation plays a significant
role in macrophage RhoA/Rho kinase signaling that decreases aggregated LDL degradation and foam cell
formation by reducing local actin polymerization required for catabolism. This may be regarded as a possible
anti-atherosclerotic effect. Proline/serine-rich coiled-coil 1 overexpression reduced foam cell formation
trough decrease of intracellular cholesterol and increase of cholesterol efflux by upregulating the expression
[21]
of peroxisome proliferator-activated receptor γ and liver X receptor α .

A flavonoid from the Morus alba L., Kuwanon G, inhibits both cholesterol accumulation and inflammation
[22]
reaction in macrophages stimulated by oxidized LDL . Observed effects are realized through enhancing
LXRα-ABCA1/ABCG1 pathway and inhibiting NFκB activation. Anti-atherosclerotic effect of Kuwanon G
was confirmed in vivo. In the plaque of high-fat diet fed ApoE -/- mice, Kuwanon G significantly reduces the
atherosclerotic areas and macrophage content. Nuclear factor erythroid 2-related factor 2 (Nrf2) prevents
[23]
foam cells formation . On the other hand, the loss of Nrf2 in macrophages enhances foam cell formation
and promotes early atherogenesis. Isolated from the root of Salvia miltiorrhiza Bge., Tanshindiol C, an
[24]
activator of Nrf2 in macrophages, markedly suppresses foam cell formation induced by oxidized LDL .
Liver kinase B1 suppresses foam cell formation and atherosclerosis development. On the contrary, down-
regulation of liver kinase B1 in macrophages results in such atherogenic manifestations as increased uptake
[25]
of modified lipoproteins, increased foam cell formation, and, finally, increased atherosclerosis .
Antibodies to specific epitopes of oxidized LDL suppress both inflammatory cytokine production and foam
cell formation [26,27] .

Endogenous human vascular endothllial growth factor (VEGF) inhibits foam cell formation. VEGF-treated
macrophages significantly decreased lipid accumulation caused by oxidized trough down-regulation of
[28]
CD36 expression .

The studies of agents that promote foam cell formation provide novel insights into their pro-atherogenic
effects under pathological conditions and suggests that their inhibiting may represent a new approach for
treating atherosclerosis. The following is a couple of examples of such studies. Hypoxia-inducible lipid
droplet-associated protein was shown to be highly expressed in atherosclerotic foam cells in human and