Open Journal of Endocrine and Metabolic Diseases, 2013, 3, 9-17
doi:10.4236/ojemd.2013.34A1002 Published Online August 2013 (http://www.scirp.org/journal/ojemd)
Intracellular Cholesterol Retention—New Target for
Direct Anti-Atherosclerotic Therapy*
Alexander N. Orekhov1,2
1Institute for Atherosclerosis Research, Skolkovo Innovative Center, Moscow, Russia
2Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, Moscow, Russia
Email: a.h.opexob@gmail.com
Received April 24, 2013; revised May 24, 2013; accepted June 24, 2013
Copyright © 2013 Alexander N. Orekhov. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
Accumulation of cholesterol in arterial cells, intracellular cholesterol retention, may be responsible for all major mani-
festations of atherosclerosis on a cellular level. Previously we have shown that intracellular cholesterol retention is the
principal event in the genesis of atherosclerotic lesions. This allows us to consider cellular retention of cholesterol as a
novel target for anti-atherosclerotic therapy. In this case the target is not the level of blood cholesterol but the level of
cholesterol in vascular cells. This review describes our approach based on the use of cultured human arterial cells for
the development of direct anti-atherosclerotic therapy. We use natural products as the basis of promising drugs for
anti-atherosclerotic therapy. Using natural products, we have developed an approach to prevent intracellular cholesterol
retention in cultured cells. Our knowledge of the mechanisms of atherosclerosis is the foundation on which we have
developed drugs that have a direct anti-atherosclerotic effect, namely Allicor on the basis of garlic powder, anti-in-
flammatory drug Inflaminat (calendula, elder, and violet) possessing anti-cytokine activity and phytoestrogen-rich drug
Karinat (garlic powder, extract of grape seeds, green tea leaves, hop cones, β-carotene, α-tocopherol, and ascorbic acid).
Treatment with allicor or inflaminat has a direct anti-atherosclerotic effect on carotid atherosclerosis in asymptomatic
men. Karinat prevents the development of carotid atherosclerosis in postmenopausal women. Thus, the main findings of
our basic research have been successfully translated into clinical practice. As a result, this translation, a novel approach
to the development of anti-atherosclerotic therapy, has been established. Our clinical trials have confirmed the sui-
tability of innovative approach and the efficacy of novel drugs developed on the basis our methodology.
Keywords: Allicor; Anti-Atherosclerotic Therapy; Atherosclerosis; Cell Culture; Drugs; Imaging; Natural Products
1. Introduction
The only hypothesis that has received confirmation in the
clinic is the cholesterol hypothesis. This hypothesis was
proposed more than 100 years ago by Nikolai Anitsch-
kow. The Anitschkow’s hypothesis linked atherosclerosis
with high levels of total cholesterol in the blood. The mo-
dern paradigm only explains some aspects of this hypo-
thesis, in particular, as atherosclerosis is not associated
with the total level of cholesterol but with atherogenic
low-density lipoprotein (LDL) cholesterol and anti-athe-
rogenic high-density lipoprotein (HDL) cholesterol [1-3].
Furthermore, the role of different molecules involved in
lipoprotein metabolism is discussed.
Retention of intracellular lipids or lipidosis that is the
accumulation of cholesterol and other lipids in the arte-
rial cells is the most prominent manifestation of athero-
sclerosis at the arterial cell level. Retention of intracellu-
lar cholesterol is accompanied by increased proliferative
activity of vascular cells and increased synthesis of ex-
tracellular matrix [4,5]. Both proliferation and fibrosis
are characteristic features of atherosclerosis at the arterial
cell level, too. Thus, intracellular cholesterol retention,
may be responsible for all major manifestations of athe-
rosclerosis on a cellular level. This allows us to consider
cellular retention of cholesterol as a novel target for anti-
atherosclerotic therapy. In this case the target is not the
level of blood cholesterol but the level of cholesterol in
vascular cells.
This review summarizes the mechanisms of intracel-
lular retention of cholesterol. We describe our cellular
models to search for anti-atherosclerotic agents, and de-
monstrate our successful attempt to use these models to
develop effective anti-atherosclerotic drugs.
*Conflict of interest: The author confirms that this article presents no
conflicts of interest.
Copyright © 2013 SciRes. OJEMD
A. N. OREKHOV
10
2. Mechanisms of Intracellular Cholesterol
Retention
Intracellular retention of cholesterol can be induced by
LDL. However, native lipoprotein usually does not in-
crease the cholesterol content of the cell but the incuba-
tion of cell cultures with chemically modified LDL re-
sults in a massive accumulation of cholesterol in the cells
[6]. Thus, modified, but not native, LDL is the source of
lipids that accumulate in arterial cells. Cells that populate
atherosclerotic lesions are overloaded with lipids, and
their cytoplasms are almost completely filled with lipid
inclusions [7]. These cells are referred to as foam cells
because of foamy appearance under microscope.
In the blood plasma of patients with coronary athero-
sclerosis we have discovered modified desialylated LDL
[8-11]. This naturally occurring LDL induces cholesterol
retention in cultured arterial cells [8-11]. Circulating mo-
dified LDL is multiple modified lipoprotein possessing
lower sialic acid, triglyceride and cholesterol contents;
smaller particle size; greater density and negative charge;
higher aggregative activity; and some other specific fea-
tures [12]. In patients’ blood we have discovered an en-
zyme, trans-sialydase, that is responsible for the desialy-
lation of LDL particles in the blood [13].
In addition to desialylated LDL, more electronegative
LDL and small dense LDL have been discover in human
blood by other researchers [14,15]. A cooperative com-
parative study showed that the more electronegative LDL
isolated by ion-exchange chromatography is desialylated
LDL [16]. On the other hand, desialylated LDL isolated
from patient blood [8-11] is more electronegative. De-
sialylated LDL particle is smaller and denser than that of
native LDL [17]. On the other hand, small dense LDL
isolated from patients has a low content of sialic acid, i.e.,
it is desialylated [18]. Glycosylation is a type of in vivo
LDL modification in the blood of patients with diabetes
mellitus [19]. This LDL is also atherogenic causing in-
tracellular cholesterol retention [20]. Oxidation is likely a
type of atherogenic modification of LDL, however, there
is no direct evidence of the presence of oxidized LDL in
blood [21].
Modified LDL stimulates anti-LDL auto-antibodies
production [22-24]. The interaction of anti-LDL auto-
antibodies with modified LDL results in the formation of
LDL-containing circulating immune complexes [25]. Mul-
tiple modified LDL, which enters the cells as a compo-
nent of immune complexes, possesses a higher athero-
genic potential compared with free modified lipoprotein;
that is, it induces a more intense intracellular cholesterol
retention [25,26]. We have found LDL-containing circu-
lating immune complexes and anti-LDL auto-antibodies
in the blood of most atherosclerotic patients [27-29]. We
have demonstrated a positive correlation between the le-
vels of LDL-containing immune complexes and the se-
verity of atherosclerosis [27-31]. LDL is able to form
complexes with cellular debris, collagen, elastin, and pro-
teoglycans of the human aortic intima [32-37]. These
LDL-containing complexes stimulate intracellular chole-
sterol retention causing increased uptake and decreased
intracellular degradation of lipoproteins in complexes
[36]. Naturally occurring multiple modified LDL forms
self-associates under cell culture conditions, while native
LDL does not associate [35]. We have found a positive
correlation between the atherogenic activity of modified
LDL and the degree of LDL self-association [35,36].
LDL-associates isolated by gel filtration were shown to
induce a dramatic intracellular cholesterol retention. The
removal of LDL-associates from the incubation medium
by filtration through filters with a pore diameter of 0.1
µm completely prevented intracellular cholesterol reten-
tion [36]. We can conclude that the formation of large
LDL containing complexes (self-associates, immune com-
plexes, and complexes with connective tissue matrix) is a
necessary and sufficient condition for intracellular cho-
lesterol retention.
Our knowledge of mechanisms of intracellular choles-
terol retention allowed us to identify possible targets for
anti-atherosclerotic therapy. Target 1 is atherogenic mo-
dification (desialylation) of the LDL particle in blood.
Target 2 is selective removal of modified LDL from
blood. Target 3 is the prevention of modified LDL ac-
cumulation in arterial cells. Target 4 is the removal of
excess lipids from foam cells. We have used all four ap-
proaches to anti-atherosclerotic therapy. All of them were
effective, however, the most suitable approach is the
third, namely, the prevention of modified LDL accumu-
lation in arterial cells. i.e. the initial step in intracellular
cholesterol retention. We use this approach for the deve-
lopment of anti-atherosclerotic therapy.
3. Development of Anti-Atherosclerotic
Drugs Preventing Intracellular
Cholesterol Retention Using Cellular
Models
We use primary culture of human aortic cells for the
screening of potential drugs, the investigation of their
mechanisms of action, and the optimization of anti-athe-
rosclerotic drug therapy.
Cells are isolated from the subendothelial part of the
human aortic intima between the endothelial lining and
the media [38]. Using collagenase and elastase, viable
cells are isolated from the subendothelial layer of the in-
tima [39-41]. Isolated cells can be classified as the mix-
ture of smooth muscle cells, pericyte-like cells, and ma-
crophages [38-42]. The culture on which our experiments
are performed is represented by this mixed population
Copyright © 2013 SciRes. OJEMD
A. N. OREKHOV 11
[38].
Cells isolated from atherosclerotic lesions retain all
major characteristics of atherosclerotic cells when cul-
tured. They are capable of synthesizing collagen, prote-
oglycans and other components of the extracellular ma-
trix [4]. Cell cultured from fatty lesions have an enhan-
ced proliferative activity [43], higher than that of cells
cultured from unaffected intima [43,44]. Considerable
part of cells cultured from atherosclerotic lesions are
foam cells, which contain numerous inclusions, likely li-
pid droplets, that fill the entirety of the cytoplasm [40].
Excess lipids in foam cells are mainly free cholesterol
and cholesteryl esters [40]. It is important that the con-
tent and composition of lipids in cultured cells within the
first 10 - 12 days in culture remain unchanged and corre-
spond to the respective indices of freshly isolated cells
[40,44]. Thus, our investigations are carried out directly
on exactly those cells that require a therapeutic action in
vivo. Using this model, we have examined the effects of
different drugs and chemicals.
The prevention of intracellular cholesterol retention
may be regarded as anti-atherosclerotic effect. In terms
of arterial cells, any drug effect that does not directly
prevent intracellular cholesterol retention is regarded as
an indirect anti-atherosclerotic action. Only a drug that
exhibits its preventive activity at the arterial level is a di-
rect anti-atherosclerotic drug.
Naturally, the question arises whether the anti-athero-
sclerotic effects revealed in in vitro cellular model can be
manifested in vivo. To answer this question, an ex vivo
model was developed. In the ex vivo model, instead of
agents, blood sera taken from patients after oral drug ad-
ministration is added to cultured cells.
4. Natural Products
Ex vivo cellular model can be used to test foodstuffs. We
have investigated prevention of intracellular cholesterol
retention caused by certain mushroom species and sea
products.
Extracts from 20 Korean mushroom species exhibit
intracellular cholesterol retention revealed by cell culture
test [45]. Among sea products, mollusk and krill meat
were investigated. Two hours after a single dietary load
with canned meat of a mollusk belonging to the genus
Buccinum, the patient’s blood serum acquired marked
anti-atherosclerotic properties (Table 1). Incubation of
this serum with cultured atherosclerotic cells led to a fall
in intracellular cholesterol retention. Patients of another
group received a single dietary dose of Antarctic krill
meat. Two hours later, the retention of cellular choles-
terol induced by blood sera decreased, and four hours la-
ter, it was practically absent (Table 1).
To develop a dietary therapy based on the krill meat,
Table 1. Effects of sea products on atherosclerosis-related
properties of patients’ plasma.
Intracellular cholesterol content, µg/mg cell protein
Product
Control 0 hours 2 hours 4 hours
Buccinum196 + 17204 + 16 181 + 19 150 + 16*
Krill 37 + 5 86 + 4 71 + 7 49 + 4*
*Significant difference from 0 hr (p < 0.05). From [46].
the effective dose and proper regimen have been es-
tablished. The anti-atherosclerotic activity of krill meat
was evaluated by the ability to reduce intracellular cho-
lesterol retention. The dose-effect dependence was re-
vealed by comparing the efficacy of the two doses, and
we found that krill meat possesses anti-atherosclerotic
effects at a dose of 10 - 20 g, half-maximum effect was
reached at a dose of 30 g, and the maximum effect was
achieved at a dose of 50 g. We believe that this approach
will be useful in the development and optimization of
anti-aterhosclerotic dietary therapies.
4.1. Botanicals
The anti-atherogenic effects of dietary products promote
the development of anti-atherosclerotic therapies based
on natural products. Atherosclerosis develops over many
years, so anti-atherosclerotic therapies should be long-
term or even lifelong. For such long-term therapies, con-
ventional medicine will not work. Drugs based on natural
products can be a good alternative.
We have tested numerous natural products’ extracts to
reveal their effects on blood atherogenicity or their capa-
city to prevent intracellular cholesterol accumulation caus-
ed by atherogenic blood sera from patients. Table 2 pre-
sents only the effective natural products. Naturally, the
tested agents included anti-atherogenic, pro-atherogenic,
and neutral products. Among the anti-atherogenic natural
products, the most effective was garlic.
We investigated the in vitro effect of garlic extract on
lipids of cultured human aortic cells. Garlic prevented the
serum-induced accumulation of free cholesterol and re-
duced the accumulation of cholesteryl esters [47]. The
effect of garlic on the enzymes responsible for the intra-
cellular metabolism of cholesteryl esters was studied. We
have shown that garlic inhibits acyl-CoA: cholesterol acyl-
transferase, which participates in cholesteryl ester forma-
tion, and stimulates cholesteryl ester hydrolase, which
degrades cholesteryl esters [47].
Further investigations ex vivo and in vivo confirmed
the in vitro effects of garlic [48]. These data stimulated
us to develop a drug based on garlic powder and carried
out a clinical study of the effects of this drug on athero-
sclerosis regression.
Copyright © 2013 SciRes. OJEMD
A. N. OREKHOV
12
Table 2. Anti-atherosclerotic effects of natural products.
Product Intracellular cholesterol
retention decrease, %
Salsola collina 11
Allium cepa 21
Beta vulgaris 31
Spirulina platensis 51
Pinus sylvestris 52
Triticum vulgaris 70
Glycyrrhiza glabra 55
Allium sativum 77
From [46].
4.2. Allicor (Garlic Tablets)
We have developed the time-released garlic powder tab-
lets Allicor, registered and produced by INAT-Farma,
Ltd. (Russia). The AMAR study (Atherosclerosis Moni-
toring and Atherogenicity Reduction) was designed to
estimate the effect of two-year treatment with Allicor on
the progression of carotid atherosclerosis in asympto-
matic men in a double-blinded, placebo-controlled ran-
domized clinical trial (ClinicalTrials.gov Identifier,
NCT01734707). The primary outcome was the rate of
atherosclerosis progression, measured by high-resolution
B-mode ultrasonography as the increase in carotid inti-
ma-media thickness (CIMT) of the far wall of common
carotid arteries [49].
The overall dynamic of changes in prevention of in-
tracellular cholesterol retention (decrease of blood serum
atherogenicity) is presented in Figure 1. At the baseline,
blood serum taken from patients induced 1.56-fold in-
crease in intracellular cholesterol content in cell culture
test. In the placebo group, the mean level of serum in-
duced intracellular cholesterol retention did not change
significantly during two years. On the opposite, in Alli-
cor-treated patients the mean value for intracellulare cho-
lesterol retention was significantly lowered already after
first 3 months of study, and this effect was maintained
during the study. We found statistically significant dif-
ference in the dynamic of changes in intracellular cho-
lesterol retention between Allicor-treated and placebo
groups.
Allicor significantly reduced CIMT compared to base-
line and the placebo group. While spontaneous athero-
sclerosis progression prevailed in the placebo group, al-
licor beneficially affected early carotid atherosclerosis,
significantly increasing lesion regression and reducing
the net number of progressive lesions. The CIMT meas-
ures were significantly different from the baseline meas-
ures and from the placebo group after the first 12 months
of treatment [49]. After two years the difference between
the placebo and allicor recipients increased and remained
statistically significant. The overall lesion progression
was clearly different in the treated and untreated patients
(Figure 2).
Our data are generally consistent with the results of a
double-blinded, placebo-controlled randomized study by
Koscielny et al. [50]. That study has been demonstrated
that 4-year treatment with the garlic-based drug Kwai in-
hibited the increase in volume of atherosclerotic plaques
in carotid and femoral arteries by 5% - 18%.
Table 3 demonstrated that the decrease in CIMT that
was achieved during the AMAR study is comparable
with the results of most successful trials with other com-
pounds [51-57]. Those studies employed potent lipid-lo-
wering agents or calcium antagonists, whose beneficial
effects of treatment were attributed to reduction in LDL
Figure 1. The dynamics of serum atherogenicity changes.
Solid circles, Allicor-treated patients; open circles, placebo
patients. *significant IMT change as compared to baseline,
P < 0.05; #significant difference from placebo group, P <
0.05. From [49].
Figure 2. Anti-atherosclerotic effects of allicor. The dynam-
ics of IMT changes. Solid circles, Allicor-treated patients;
open circles, placebo patients. *significant IMT change as
compared to baseline, P < 0.05; #significant difference from
placebo group, P < 0.05. From [49].
Copyright © 2013 SciRes. OJEMD
A. N. OREKHOV 13
Table 3. The comparative data from clinical trials on ca-
rotid atherosclerosis regression.
Mean annual IMT
change, mm
Trial
Medication Placebo Treatment
Reference
PLAC II Pravastatin 0.068 0.059 [51]
KAPS Pravastatin 0.029 0.010 [52]
ASAP Simvastatin - 0.009 [53]
PREVENT Amlodipine 0.011 0.015 [54]
ASAP Atorvastatin - 0.020 [53]
CLAS Cholestipol,
Niacin 0.010 0.020 [55,56]
MARS Lovastatin 0.015 0.028 [56,57]
VHAS Verapamil - 0.028 [58]
AMAR Allicor 0.015 0.022 [49]
From [46].
cholesterol, the major risk factor for atherosclerosis de-
velopment, or arterial wall stress.
The results of our study demonstrate that long-term
treatment with the time-released, garlic-based drug alli-
cor provides a direct anti-atherosclerotic effect on carotid
atherosclerosis. As a natural drug, allicor is safe with
respect to adverse effects and allows even perpetual ad-
ministration, which may be quite necessary for the pre-
vention and treatment of subclinical atherosclerosis. Ef-
fects of allicor promoted the start of clinical trials of two
other drugs based on natural products: Inflaminat, which
possesses anti-cytokine activity, and the phytoestrogen-
rich drug Karinat, which is designed for postmenopausal
women.
4.3. Inflaminat (Calendula, Elder, Violet)
Atherosclerosis is accompanied with elements of local
aseptic inflammation, and inflammatory cytokines play a
role at every stage of atherosclerosis development [59-
61]. Thus, anti-inflammatory drugs may be effective for
the prevention of atherosclerosis. Natural drugs are sui-
table for the early prevention of atherosclerosis because
they have almost no side effects and exert regulatory ef-
fects at physiological limits, allowing longer, almost life-
long, medication. We investigated the atherosclerosis re-
gression effect of the natural drug “Inflaminat”, which is
based on calendula, elder and violet. Our laboratory inve-
stigation demonstrated that these botanicals suppress se-
cretion of pro-inflammatory cytokines. We have carried
out a pilot study (ClinicalTrials.gov Identifier, NCT01743404)
with inflaminat using a protocol similar to that of the
AMAR study. Inflaminat demonstrated atherosclerosis
regression effects and a statistically significant difference
from the baseline as well as from placebo group [49].
Table 4 demonstrates the anti-atherosclerotic effect of
inflaminat in asymptomatic men.
4.4. Karinat (Phytoestrogen-Rich Combination)
Modern medicine does not provide an effective approach
to atherosclerosis prevention in postmenopausal women.
Hormone replacement therapy is not acceptable as a tool
for atherosclerosis prevention in women due to the nega-
tive results of clinical studies, including WHI, PEPI, and
HERS [62-67]. Phytoestrogens may be regarded as a
possible alternative to hormone replacement therapy, but
practically nothing is known about their effects on athe-
rosclerosis.
We selected phytoestrogen-rich botanicals on the basis
of their ability to prevent intracellular cholesterol reten-
tion using the above described ex vivo test system. The
following botanicals were chosen: garlic powder, extract
of grape seeds, green tea leaves, and hop cones, all of
them produced significant anti-atherogenic effects. This
combination of botanicals was used for development of
novel isoflavonoid-rich dietary supplement “Karinat”.
Karinat prevents intracellular cholesterol retention and is
characterized by an improved phytoestrogen profile, pro-
viding additional amounts of biologically active poly-
phenols, including resveratrol, genisteine, and daidzeine,
which are claimed to exert effects on atherosclerosis de-
velopment. In addition, karinat contains additional amounts
of β-carotene, α-tocopherol and ascorbic acid to provide
the necessary daily intake of antioxidants.
We have carried out a randomized, double-blinded,
placebo-controlled pilot clinical study on the anti-athe-
rosclerotic effects of karinat in healthy postmenopausal
women to characterize the risks and benefits of phy-
toestrogen therapy in relation to atherosclerosis pro-
gression (ClinicalTrials.gov Identifiers, NCT01741974
and NCT01742000). The annual rate of changes in com-
mon carotid artery intima-media thickening was moni-
tored. The effects of karinat treatment on the dynamics of
carotid atherosclerosis in postmenopausal women are de-
monstrated in Table 5. The rate atherosclerosis in post-
menopausal women was extremely high: the average in-
crease in IMT was 13% per year, and the growth of athe-
Table 4. CIMT changes in 1-year inflaminat pilot study.
Inflaminat Placebo р**
Number of
participants 81 77 -
IMT change,
μm
62 ± 48*
(91; 32)
р = 0.002
42 ± 75
(9; 93)
р = 0.109
0.002
*significant differences, p < 0.05, Wilcoxon’s signed ranked test; **statistical
significance of differences was estimated by Mann-Whitney U-test. From
[49].
Copyright © 2013 SciRes. OJEMD
A. N. OREKHOV
14
Table 5. CIMT changes in 1-year karinat pilot study on
postmenopausal women.
Karinat Р Placebo Р
Number of
participants 80 - 77 -
IMT change,
μm
+6
(85) NS +111
(91) P < 0.02
Plaques,
scores +0.21 (0.59) 0.009 +0.31
(0.55) <0.001
From [49].
rosclerotic plaques was 40% per year. In the karinat
group the average CIMT was not changed (statistically
insignificant increase of 6 μm per year, less than 1%).
The progression of existing plaques was slower by 32%
per year.
Thus, the use of the phytoestrogen-rich combination in
postmenopausal women almost completely suppresses the
formation of new atherosclerotic lesions, and it slows the
progression of existing lesions [49].
5. Conclusion
Our basic studies have shown that intracellular choles-
terol retention is the principal event in the genesis of
atherosclerotic lesions. On the basis of the results of our
basic research we developed cellular models and an ap-
proach to prevent intracellular cholesterol retention. Pre-
vention of intracellular cholesterol retention led to the
prevention of atherosclerosis progression and/or the re-
gression in patients. We can conclude that our basic find-
ings were successfully translated into clinical practice.
Two-year treatment with allicor (garlic powder) has a
direct anti-atherosclerotic effect on carotid atherosclero-
sis. Anti-cytokine combination inflaminat (calendula, el-
der and violet) caused the regression of carotid athero-
sclerosis in a 1-year treatment of asymptomatic men. The
phytoestrogen-rich combination karinat (garlic powder,
extract of grape seeds, green tea leaves, hop cones, β-ca-
rotene, α-tocopherol and ascorbic acid) prevented the de-
velopment of carotid atherosclerosis in postmenopausal
women.
Unfortunately, natural products with anti-atheroscle-
rotic therapeutic potential are not prescribed by medical
practitioners as anti-atherosclerotic agents. However, our
data allow us to consider botanicals as mainline addi-
tional supplements or prescriptions [68].
6. Acknowledgements
This work was supported by the Russian Ministry of
Education and Science.
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