Atherosclerosis is a disease that has plagued humans for thousands of years and was

proven not to simply be a recent development due to the high fat diets and more sedentary
lifestyles. Atherosclerotic lesions were found in Egyptian mummies and hunter-gatherer-fisher
mummies in Alaska. There was even an investigation done of a 5,300 year old Iceman which
provided evidence of atherosclerosis and several single nucleotide polymorphisms known to
predispose to atherosclerosis in contemporary humans (Wann et al, 2014, p. 241). Public health
efforts have attempted to address the issue and have seen a decrease in atherosclerosis. Wann et
al. (2014) provides statistical evidence writing that atherosclerosis was present in 77% of
soldiers dying from trauma in the Korean War, 45% in the Vietnam War, and 8.5% in the Iraq
War (p. 240). There is still a long way to go in reducing the morbidity so it is important to
understand the pathways that contribute to the development and exacerbation of atherosclerotic
lesions. This paper will argue that inflammation along with elevated levels of oxidized LDL
cause atherosclerosis with stress as a contributing factor. It will also provide evidence for a
connection between socioeconomic status and unhealthy lifestyle habits which lead to
atherosclerosis risk. The model below depicts factors involved in the development and
progression of the disease.

Social
Support

Low

Increased
Stress
levels
Unhealthy
diet

Elevated
Blood
Pressure and
Inflammatio
Increased
LDL levels

CVD
Or
Atherosclerosi

Lack of
physical
activity

Fig A: A theoretical model showing mediation of the association between low SES
and CVD by stress levels, elevated blood pressure, lack of physical activity,
unhealthy diet, and increased LDL levels and moderation by social support.

Atherosclerosis is a cardiovascular disease that affects the coronary arteries and begins
with a lesion to the artery. Inflammation and high levels of oxLDL cause the progression of the
lesion into more advanced stages eventually causing thrombosis. According to Luis (2000),
atherosclerosis begins with a buildup of lipids and fibrous elements in the arteries. This attracts
monocytes which are able to pass through the endothelium and into the intima due to the lesion.
The monocytes proliferate into macrophages and absorb the oxLDL turning into foam cells. This
happens with many cells and they eventually die, building up a plaque in the artery. Smooth
muscle cells form a cap over the lipid rich necrotic core and it continues to grow until it expands
into the lumen. Blood continues to supply it with mononuclear cells and eventually the lesion
becomes unstable. When thrombosis occurs this partially blocks the flow of blood or completely
shuts it off. This is dangerous because oxygen and nutrients carried in the blood cannot make it
to body cells.
An essential part of atherosclerosis is the ox-LDL which comes from high cholesterol
intake. A study done by Simons (1986) was able to demonstrate the positive correlation between

serum cholesterol levels and coronary disease mortality by gathering lipid data from multiple
different countries. Interestingly, the study found different results between men and women
presenting a possible gender specific response to high cholesterol levels. The study found a
positive correlation between serum cholesterol levels and coronary artery disease (CAD) deaths
in men as well as a positive correlation between the ratio of serum cholesterol to HDL. In women
the only correlation they found in the data was between the ratio of serum cholesterol/HDL and
CAD mortality. This correlation between cholesterol and CAD stems from the higher levels of
oxLDL which result from high cholesterol intake.
Oxidized LDL comes from LDL interacting with free radicals. These molecules then
attract monocytes to the area which take up oxLDL. A study by Zeibig et al. (2011) looked into
the mechanisms behind oxLDLs role in the progression of atherosclerosis. The authors used a
protein Fc-CD68 which binds to oxLDL to identify how this would affect plaque progression. It
mimics anti-oxLDL so it essentialy eliminates the effects of the oxLDL. They used the treatment
in mice that were fed a high cholesterol diet and found that Fc-CD68 greatly reduced plaque
progression in the aortas of those mice by about 50%. They also found that Fc-CD68 stabilized
arteries in the heart because total ruptures reduced by about 20%. The protein increased the
amount of collagen by about 1.8 times which also stabilizes the plaque and avoids thrombosis.
Finally when this protein bound to oxLDL it aided in the reduction of inflammatory cells at the
lesion site. Infiltration of lesions with lymphocytes and macrophages was decreased by about
50% and 30% respectively (Zeibig et al., 2011, p. 701). All of this points out just how important
oxLDL is to the pathway that causes progression of atherosclerosis.
Another study looks further into how ox-LDL might mediate the progression of the
plaque through certain inflammation cytokines and receptors that cause greater inflammation and
therefore progression. A study by Geng et al. (2010) studied the relationship between oxLDL and

the TLR4 pathway. TLR4 expression causes upregulation of nuclear factor-kappa B and
increased concentrations of MCP-1 and IL-8. NF-kB is of interest due to its involvement in DNA
regulation and cytokine production and survival. MCP-1 and IL-8 are factors that attract
monocytes and play an important role in atherogenesis. The study found that ox-LDL had a dose
dependent effect on TLR4 expression whereby larger doses of ox-LDL caused greater TLR4
expression. The results also showed that NF-k B activity and concentrations of MCP-1 and IL-8
increased. In order to further define the pathway the researchers used siRNA to block expression
of TLR4. When expression was blocked the NF-k B, MCP-1, and IL-8 decreased but were still
larger than the control. This suggested that the effects of ox-LDL on plaque buildup is mediated
by the TLR4 pathway. The importance of this finding is that inhibiting TLR4 expression could
indirectly slow progression of atherosclerosis.
Yet another study by Paland, Aharoni, & Furhman (2013) studied the effects of
Urokinase-type plasminogen activator on the transformation of monocytes into macrophages due
to its importance in the pathway. Macrophage uPA overexpression increases progression of
atherosclerosis using multiple mechanisms like increasing oxidative stress as well as apoptosis in
cells. First the authors questioned if uPA inhibits ox-LDL induced macrophage death. They
found, as expected, that oxLDL caused macrophage death but when in the presence of uPA death
was inhibited. The inhibition was dose dependent but peaked at 51%. Time is also important
because lesions in different stages can have different reactions to apoptosis. In early lesions it is
beneficial to cause apoptosis in the cells because this prevents progression of the lesion.
Therefore, it would not necessarily be helpful to have uPA expression inhibiting cell death. In
late stages macrophage death can cause necrosis which makes the plaque more dangerous. Yet if
the macrophages survive they will also cause the progression by secreting molecules and

transforming into foam cells which will eventually die. Other studies have demonstrates this
which is why uPA inhibition of apoptosis may be atherogenic.
From these studies it is clear that oxLDL is a huge factor in the progression of
atherosclerosis but inflammation is just as necessary in causing the disease to progress. Literature
by Ross (1999) further explains the relation. The cause of atherosclerosis used to be mostly
attributed to the concentration of cholesterol, mostly ox-LDL, but the first type of lesion is due to
inflammation. The response-to-injury hypothesis states that the lesions progress due to the
inflammation and the inflammation is caused by an original injury to the artery. This injury could
be from smoking, hypertension, diabetes, high homocysteine, infections or a combination. If the
inflammation continues the lesions progress to the more complex stage and eventually
thrombosis occurs. These injuries make the endothelium alter its ability to maintain selective
permeability which allow leukocytes or platelets to enter the walls. The inflammatory response
also causes proliferation of smooth muscle cells, a component of the plaque. As the response
continues the artery wall itself will become thicker without actually bursting into the lumen.
Eventually though the artery will become so swollen from macrophages, lymphocytes and other
fibrous tissue that it will enter into the lumen. This is when blood flow is altered and the
complicated lesion becomes truly dangerous. (Ross, 1999)
The mechanisms behind this inflammation were examined at the RNA level by Yang,
Yang, Liang, & Zhu (2015). They investigated how microRNA-155 affects inflammation through
SOCS1, STAT3 and NF-kB expression. This specific miRNA is expressed in macrophages and is
upregulated in the presence of oxLDL. They found that miR-155 in oxLDL macrophages caused
a decrease in the expression of SOCS1. From their results they concluded that miR-155
expression is inversely correlated with SOCS1 expression in oxLDL-stimulated macrophages
and in atherosclerosis mice (Yang et al., 2015, p. 1374). Inhibition of miR-155 caused a

decrease in the levels of the inflammatory cytokines TNF-a and IL-1B and the chemokines
CCL2, CCL4, and CCL7. In other words inhibiting miR-155 decreased inflammation. They also
were able to find that blocking SOCS1 expression caused increased levels of those cytokines and
chemokines as well. The authors also identified that miR-155 inhibition caused decreased
expression of STAT3 while miR-155 expression increased STAT3 expression. MiR-155 also
upregulated NF-kB in OxLDL macrophages. These two molecules are important in the
progression of atherosclerosis and are mediated by SOCS1. SOCS1 is important in
downregulating STATs which cause inflammation. After all of this data the researchers wanted to
understand if then inhibiting miR-155 would be advantageous for atherosclerotic individuals.
They blocked miR-155 expression in mice that were fed high fat diets and found that the plaque
macrophages decreased and collagen deposition increased. This suggested that the plaque area
was stabilized but they also observed a decrease in inflammation. Overall, the results
demonstrated that miR-155 promotes atherosclerosis through inhibition of SOCS1. This then
allows for high levels of STAT3 and NF-kB which cause inflamamation.
Another important factor in inflammation and subsequent atherogenesis is the F11R gene.
Cytokines can cause the upregulation of the F11R gene. This causes adhesion of circulating
platelets to the endothelium which contributes to plaque buildup. Azari et al. (2011) studied the
role of F11R first by exposing cells to proinflammatory cytokines TNF-a and IFNy. This caused
increased expression of F11R and was dose dependent. Normal endothelial cells express low
levels of F11R but when proinflammatroy cytokines TNF-a and IFNy are raised, F11R
expression also increased. An experiment was also done where NF-kB was inhibited to examine
how that pathway was effected. Previous studies had found that the NF- kB signaling pathway
causes upregulation of F11R by TNF-a. When NF- kB was inhibited the TNF-a induced
expression of F11R was also inhibited. This demonstrates that NF-kB causes increased

proinflammatory cytokines which also cause upregulation of F11R. These proinflammatory

cytokines cause not only an upregulation of F11R but a release of soluble F11R into the
extracellular medium. Other studies have found that an increase in serum F11R are associated
with an increase in cardiovascular disease risk. This further supports the connection between
F11R and plaque progression.
Another pathway in the model connects physical activity to atherosclerosis. Shai et al.
(2010) investigated how different physical activity levels could affect levels of cytokines, blood
pressure, and other factors involved in atherogenesis. This was a three year study in which they
were able to follow activity levels of participants and gather data every month. They found that
physical activity decreased concentration of the inflammatory cytokine TNF-a and slightly
decreased IL-6. The researchers also measured C-reactive protein (CRP) levels due to its action
in endothelial dysfunction. Physical activity greatly decreased this protein which is beneficial
because CRP increases reactive oxygen species and NF-kB. As described previously NF-kB
causes increased cytokines and chemokines which increases risk of atherosclerosis progression.
The most important finding was the decrease in TNF-a because it effects atherosclerosis in
multiple different ways including inflammation, oxidative stress, and apoptosis. All of these
progress the lesions of atherosclerosis and would eventually lead to thrombosis. The researchers
explained that their findings also showed that physical activity caused a decrease in the cytokine
IFN-y which is involved with macrophage activation and plaque destabilization.
Another cause of atherosclerosis that is depicted in the model is chronic stress. Many
Americans face stressors everyday due to the achievement oriented and high pressure culture of
America. A study by Xiao-Ting et al. (2012) on high cholesterol-fed rabbits was able to
demonstrate how chronic mild stress predicted the plaque formation. In this study the rabbits
were all fed a high cholesterol diet and the experimental group was placed under a stressor every

day. The stressor was either acoustic irritation, restrain stress, inversion of light/dark cycle, or
cage suspending. These all were shuffled randomly to avoid habituation. As expected the high
cholesterol diet (HD) caused formation of atherosclerotic plaques while regular fed rabbits
showed no plaques. The significant finding is that in the HD animals the chronic stressor
significantly increased the size of the plaques. Specifically the authors found that stress caused
an increase in the amount of macrophages and expression of MMP-2 and MMP-9. The smooth
muscle cells and collagens were decreased compared to the non-stressed animals but the stressor
group also showed plaque cell apoptosis while the other did not. All of this data clearly
demonstrates that the chronic mild stressor greatly accelerated the plaque formation and also
destabilized the plaques making them more dangerous to health (Xiao-Ting et al, 2012).
Another study by Nordstrom, Dwyer, Noel, Shircore, & Dwyer (2001) that used humans
found very similar results. This study examined the effect of workplace stress on carotid lesions
and carotid thickening in men and women. In order to measure work-related stress each
participant did a questionnaire designed to determine the demand of the job as well as the
ability to separate work from home life. Their results showed that 20.7% of men in the lowest
quintile of stress had carotid lesions while 36.4% of men in the highest quintile of stress had
lesions. This was a strong correlation which led the authors to believe that work stress does
increase likelihood of carotid lesions. Other research did not have such distinct results but the
measurements of stress were very different. More research must be done in order to properly
define how stress affects lesion development in men and women.
Finally the model depicts a connection between socioeconomic status and physical
activity as well as diet. Lower SES can result in a great number of barriers for those who want to
remain healthy. Supermarkets providing fresh foods are not always close by and many

individuals do not have time for regular exercise. There are many other factors such as
environment and psychological factors that also play into these relationships but this study
focused in on just a few. Blane et al. (1996) focused on employed people in all levels of
employment and were given a questionnaire and physical examination. They then analyzed
diastolic blood pressure, serum cholesterol concentration, recreational physical exercise,
cigarette smoking and others. They discovered that higher diastolic blood pressure and less
physical activity were correlated with lower socioeconomic status. This is comparable to
previous studies because it shows lower socioeconomic positions are at greater risk for coronary
artery disease like atherosclerosis. The data was examined based on fathers social class as well
as own social class to determine how the factors were correlated to childhood or adulthood as
well. Recreational physical activity and a cigarette smoking were associated with higher CAD
risk within own social class but not fathers. The authors noted that these were very behavioral
risk factors which could suggest such factors are more linked to adulthood. Serum cholesterol
concentrations were graded in the opposite direction of CAD risk. The authors pointed out that
the data for CAD was older data and this counter gradient for cholesterol may be disappearing
(Blane et al., 1996, p. 1436). Overall it was found that lower socioeconomic status can result in
lower physical activity and higher blood pressure causing greater risk for coronary artery disease.
The model has extensive data to support the pathways it depicts as shown above.
Socioeconomic status is correlated with higher blood pressure as well as lack of physical activity.
Inflammation and increased LDL, specifically oxLDL, are greatly involved in the progression of
atherosclerosis and have complex mechanisms that mediate their effect. Furthermore, stress
levels do cause a greater chance of atherosclerosis due to their effects on inflammation.
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