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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 5, September/October 2017
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AFRICA
that up-regulation of LDL receptors on the cell surface is
another event that consequently leads to decreased plasma levels
of atherogenic LDL particles.
21
On other hand, based on our findings, cholesterol-induced
oxidative stress in the form of plasma oxLDL could be decreased
by AV administration, which was confirmed by prior studies.
30
Zhang
et al
. indicated that AV prevented oxLDL-induced
oxidative stress in cardiomyocytes via a decrease in plasma
levels of oxLDL, inhibition of expression of LOX-1 as oxLDL
receptors, and apoptosis.
30
More recently, Mason
et al.
showed
that
in vitro
eicosapentaenoic acid (EPA), a triglyceride-lowering
agent, inhibited LDL oxidation, and the addition of AV at low
concentrations enhanced this inhibition.
31
Accumulating data from
in vitro
and
in vivo
models support
the pro-atherogenic role of oxLDLs via: (1) recruitment of
polymorphonuclear cells, promoting their transformation into
foam cells; (2) induction of the proliferation of smooth muscle
cells (SMCs) in the tunica intima; and (3) promotion of
apoptosis in the endothelial cells, SMCs and macrophages.
6
Therefore the oxLDL-lowering potential of AV leads to clinical
benefits by attenuating cardiovascular events.
32
Reduction in oxLDL levels subsequently controls its
downstream effectors, such as stress kinases of p38 MAPK and
JNK, which consequently reduce scavenger receptors and foam
cell formation.
33
Confirming previously reported evidence,
14,21,32
in our experiments, AV down-regulated cholesterol-induced p38
phosphorylation, which is a pro-inflammatory marker and stress
kinase, in the carotid homogenate of hypercholesterolaemic
rats. In line with our results, in a concomitant study on the
effects of ATO on thrombomodulin (TM), which is critical
for vascular thromboresistance, Lin
et al
. showed in the
aorta of cholesterol-fed rabbits, that statins could protect
the vasculature from p38-mediated inflammatory damage and
that atherosclerosis resulted from cholesterol-dependent or
independent mechanisms.
34
In the study by Rutishauser
et al.
, they showed the beneficial
effects of statins on hypertension-induced vascular damage by
inhibition of angiotensin II-induced intracellular responses,
containing p38 MAPK and RhoA/ROCK activation.
19
In another
study, researchers showed that oxidative stress induced NADPH
oxidase production, and p38 MAPK signalling was prevented
by statin treatment.
35
As shown in Fig. 3, cholesterol-induced
cleavage of caspase-3 in carotid tissue suggests that activation
of the caspase-dependent apoptotic pathway could be negatively
influenced by AV, which is similar to the results of our study.
Chen
et al
., in an experimental rat model of acute myocardial
infarction, showed that AV improved left ventricular function
and decreased infarct size compared with the control group,
along with reduction in the index of cell apoptosis.
36
Apoptosis
is a central component in the pathophysiology of atherosclerosis
and is mediated by extrinsic or intrinsic signalling pathways.
Bcl-2 proteins act as the major mediators of both apoptosis
signalling pathways. Recently it has become clear that they
regulate apoptosis in vascular cells following oxidative and
inflammatory events, not only by down-regulation of anti-
apoptotic proteins of Bcl-2 but also by up-regulation of the
pro-apoptotic protein of Bax or Bad proteins.
23
Other findings in our study were that restoration of the
anti-apoptotic protein of Bcl-2 occurred after administration of
AV. This result is in agreement with previous studies.
8,30
Kutuk
et al.
considered Bcl-2 protein an important target drug in
the treatment of atherosclerosis.
16
The study by Fröhlich
et al
.
indicated that Bcl-2 had a protective role in fully differentiated
ReNcell VM cells.
8
However, in the study by Peng
et al.
,
inhibition of the proliferation of PC3 human prostate cancer
cells has been shown via negative regulation of Bcl-2 and positive
regulation of p21.
9
The endoplasmic reticulum (ER), as an important cellular
organelle, is implicated in various vital functions of cells,
10
such
as protein folding and translocation,
11
lipogenesis and control
of calcium balance.
12
The Bcl-2 family, which is found in the
ER, controls the many signalling pathways and therefore cell
survival.
13
ER-situated anti-apoptotic proteins such as Bcl-xL
and Bcl-2 prevent the effect of a wide range of apoptosis
inducers.
18
Mitochondrial and ER apoptosis signalling pathways
can lead to cleavage and activation of caspase-3, a major killer
caspase.
18
The definite output of caspase-3 cleavage is DNA
fragmentation, and subsequently programmed cell death.
16
Conclusion
The findings of our study, including the beneficial effects of
atorvastatin in the suppression of cholesterol-induced cleaved
caspase-3 and the concomitant elevation of Bcl-2 and reduction
of phosphorylated p38 MAPK, suggest that the anti-apoptotic
effect of atorvastatin may be partially mediated by either p38
MAPK or Bcl-2.
18,22
They also suggest that p38 MAPK, a
pro-inflammatory protein and Bcl-2, an anti-apoptotic protein,
could be targeted in the prevention of cholesterol-induced
atherosclerotic events in the carotid tissue by atorvastatin.
We thank Dr Farhoudi, head of the Neurosciences Research Centre, Tabriz
University of Medical Sciences, Tabriz, Iran, for providing the facilities for
our experiments.
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