Page 225 - Read Online

Sobenin. Vessel Plus 2020;4:18 I http://dx.doi.org/10.20517/2574-1209.2020.09 Page 3 of 6

accumulation in cells as the initial and key step in the formation of atherosclerosis lesion [9,10] . However,
LDL must first undergo proatherogenic modification, rendering it atherogenic i.e. capable of inducing
intracellular lipid deposition [11-14] and this requires interactions between lipoproteins and connective tissue
matrix components of the intima. In turn, this leads to retention of lipoproteins in the arterial intima,
which increases the possibility of further interaction with intimal cells [15,16] to undergo complex cellular
reactions such as the binding and internalization of modified lipoproteins, and abnormal intracellular
processing, culminating in foam cell formation [4,10,17,18] . In parallel, intimal cells also exhibit a proliferative
burst, increased synthesis of proteins and the components of connective tissue matrix, a pro-inflammatory
response with the synthesis and secretion of cytokines, and the presentation of bound lipoproteins as
autoantigens [4,19] . Thus, all the major characteristics of early atherosclerosis (lipidosis, fibrosis, proliferation
and inflammation) are demonstrated at the cellular level at this stage of atherogenesis. In cases of relatively
successful resolution of the cellular reaction to pathogenic lipoproteins, early lesions may either undergo
spontaneous regression, or transform into stable atherosclerotic plaques. Such a result should be considered
as compensatory arterial remodeling. On the other hand, an adverse outcome is characterized by a chronic
inflammatory response, recruitment of immunocompetent cells from the circulation, and a vicious cycle of
lipid accumulation in the arterial wall [20-22] . This unfavorable result will lead to growth of the atherosclerotic
plaque, development of new lesions and plaque instability that will in turn, manifest as a clinical event.

Certainly, such schema is rather straightforward and oversimplified. It does not account for some
mechanisms, such as the effectiveness of reverse cholesterol transport, high density lipoprotein (HDL)
functioning, immunogenicity of modified LDL, the formation of atherogenic LDL-containing immune
complexes, thrombotic events, etc., all of which have a role in atherogenesis. However, this scheme allows
to demonstrate the unresolved issues with our knowledge on the molecular and cellular mechanisms of
atherogenesis, i.e. those “white spots”, which obviously need further in-depth investigations.

The only existing paradigm in the prevention and treatment of atherosclerosis is extensive lipid lowering.
This idea is based on the role of circulating lipoproteins as the source of cholesterol and as a key player in
initializing atherogenesis. Thus, all current medical approaches are based on improving the lipid profile
of blood plasma (lowering LDL cholesterol and triglycerides and increasing HDL cholesterol) and aims to
eliminate major lipid risk factors for atherosclerosis. The development of alternative approaches for anti-
atherosclerotic therapy through the targeting of other key pathogenetic mechanisms is extremely difficult
due to the lack of fundamental knowledge on potential molecular and cellular targets for therapy and
prevention. Among the latter are endothelial dysfunction and local violation of the permeability of the
endothelial barrier, atherogenic modification of lipoproteins, retention of lipoproteins in the subendothelial
intima of the arteries, alternative pathways of lipoprotein uptake by intimal cells, fibrotic and proliferative
responses of intimal cells to modified lipoproteins, specificity of the reaction of different cells populating
the intimal layer (smooth muscle cells, pericyte-like cells, macrophages, lymphocytes, other cells that
migrated from circulation), the development of a local inflammatory reaction, ineffective resolution of
local inflammation, local reaction of innate immunity, mitochondrial dysfunction, and the mechanisms for
stabilization of atherosclerotic plaque and remodeling, etc. [Figure 1].

One of my own research interests is the mitochondrial genetics of atherosclerosis. There are several reasons
for considering mutations occurring in mitochondrial DNA (mtDNA) as the mechanistic factor involved
in atherogenesis. Atherosclerosis may be considered as an age-related degenerative pathology, accompanied
by cell senescence which is generally characterized by reduced cell proliferation, irreversible growth arrest
and apoptosis, epigenetic modifications, shortening of telomere length, increased mtDNA damage, and
[23]
mitochondrial dysfunction . The structural alterations of mitochondria and mtDNA damage are the most
[24]
evident signs of mitochondrial aging . Mutations of the mitochondrial genome can lead to structural
defects in some energy-generating enzymes and transfer RNAs (tRNAs) synthesized directly in the