Exercise on OxLDL and Atherosclerosis

Exercise on OxLDL and Atherosclerosis 1

Running head: EXERCISE ON OXLDL AND ATHEROSCLEROSIS

The Influence of Aerobic Exercise on OxLDL and Subsequent Implication on Atherosclerosis

April 16, 2010

Michael Rosenblat

Email: [email protected]

Student ID: 0180673

Faculty Advisor: Dr. Drew Graham

University of Guelph


Contents 1.0 Reactive oxygen species 1.1 What are ROS? 1.2 ROS production 1.3 Function of ROS 1.4 Significance of ROS 2.0 ROS and endothelial function 2.1 ROS and vascular signaling 2.2 ROS and inflammatory cytokines 2.3 ROS and adhesion molecules 2.4 Potential implications of ROS, endothelial function with atherosclerosis 3.0 ROS and LDL 3.1 What is LDL? 3.2 Oxidation of LDL and ROS production 3.3 OxLDL and eNOS 3.4 OxLDL and vascular remodeling 3.5 OxLDL and inflammation 3.6 Significance of LDL and OxLDL with atherosclerosis 4.0 Aerobic exercise on ROS and antioxidant formation 4.1 Significance of aerobic exercise 4.2 Aerobic exercise and ROS formation 4.3 Aerobic exercise and antioxidant formation 4.4 Aerobic exercise on vascular function 5.0 Aerobic exercise on LDL and OxLDL 5.1 Review significance of LDL and OxLDL with atherosclerosis 5.2 Aerobic exercise on LDL 5.3 Aerobic exercise on oxidation of LDL and OxLDL 6.0 The effects of aerobic exercise on atherosclerosis


Introduction

Cardiovascular disease (CVD) accounts for 29% of all human mortality and is the leading

cause of death worldwide (6). Atherosclerosis is one of the most significant cardiovascular

diseases (52) and is associated with a number of metabolic disorders including diabetes (17),

dyslipidemia (16) and obesity (42). It is apparent that with the current aging population and the

rise in obesity in developed countries, the prevalence of atherosclerosis will continue to increase.

Atherosclerosis is an inflammatory disease that leads to the development of arterial

plaque and stenosis (9). The exact mechanism that initiates the inflammatory response is still

unknown, however, considerable evidence suggests that there is a link between

hypercholesterolaemia and reactive oxygen species (ROS), with markers of inflammation (23,

39, 44). Pro-inflammatory cytokines (eg. TNF-α, IL-6) induce the expression of cellular

adhesion molecules (eg. VCAM-1), leading to the attachment of monocytes to the endothelial

wall, and their subsequent entrance into the vascular tissue (45). Once inside the media (inner

arterial layer), macrophages (derived from the monocytes) consume lipoproteins and transform

into foam cells, forming the initial atherosclerotic lesion (44).

Modified lipoproteins, more specifically oxidized-low-density lipoproteins (OxLDL),

greatly contribute to the development of endothelial dysfunction and atherosclerosis (23).

OxLDL-induced formation of ROS leads to vascular remodeling (proliferation, hypertrophy,

apoptosis, etc.); plaque instability; and an alteration in endothelial nitric oxide synthase (eNOS)

decreasing nitric oxide production (23, Also See Figure 1). These vascular responses lead to

increased levels of pro-inflammatory cytokines, as well as, cellular adhesion molecules (39). As

a result, it is clear that OxLDL significantly alters endothelial function, promoting atherogenic


conditions and furthering the development of the disease (Figure 2 illustrates the progression of

endothelial dysfunction with atherogenesis).

Acknowledging the significance of OxLDL and its role in the development of

atherosclerosis, a number of treatment methods can be employed to modify the progression of

the disease. These methods include the use of pharmaceuticals, nutrition, and exercise

interventions. Aerobic exercise in particular can have a considerable impact on the formation and

effects of OxLDL (4). Physical activity has been shown to decrease oxidative stress; increase

tissue antioxidant levels; protect lipoproteins from oxidative damage; and decrease LDL levels

and concurrently increase high-density lipoprotein (HDL) levels (4).

There are some studies, however, that indicate that cardiovascular exercise may have

negative implications on the markers of oxidative stress. Since these studies use a variety of

exercise programs, it is essential to analyze the effects of various exercise intensities and

durations on OxLDL. Ongoing research highlights the need to review atherosclerosis with a view

to strengthening the focus on the interrelationship between aerobic exercise and OxLDL as they

pertain to the pathophysiology of this disease. The major topics covered in this review include: a

general background on ROS; ROS and endothelial function; ROS and low-density lipoprotein

cholesterol (LDL-C); aerobic exercise on ROS and antioxidant formation; aerobic exercise on

LDL oxidation; and the effects of aerobic exercise on atherosclerosis.

Reactive Oxygen Species (ROS)

In order to analyze the effects of ROS on endothelial function and atherosclerosis, it is

important to establish a clear understanding of what ROS are and their relevance in human

physiology and pathology. ROS is a term that is used to describe O2- derived free radicals that

are highly reactive. These free radicals are considered to be reactive because they possess one or


more unpaired electrons, causing them to alter the activity of other atoms or molecules. Oxygen

(O2) which is the most common of all biologically important chemical species, is a major source

of ROS (71). The process of reducing O2 by a single electron leads to the formation of

superoxide anion (O2.-), one of the most common free radicals that is produced in human cells

(57). Some of the other more frequently occurring reactive O2 derived free radicals include

hydroxyl (HO.), peroxyl (RO2.), and alkoxyl (RO.). There are also nonreactive O2 species of

which the most common is hydrogenperoxide (H2O2) (28).

ROS generation is a constant biochemical process that occurs in most biological tissues

(81). The formation of ROS and the locations where it occurs is significant because these factors

dictate the physiological effects that these biomolecules have on the neighbouring tissues. Since

the focus of this review is primarily on vascular tissue, it is crucial to discuss the various sources

of vascular ROS generation.

There are both enzymatic and nonenzymatic processes by which oxygen species can be

formed within the vasculature. The most significant enzymatic sources include NAD(P)H-

oxidase (Nox), Xanthine oxidase (XO), and uncoupled eNOS (23). Conversely, the major

sources of nonenzymatic vascular ROS formation primarily occur through oxidative metabolism

in the mitochondria, more specifically from complex I and complex III of the electron transport

chain (10).

While it is clear that discussing vascular tissue with respect to ROS is important, it is also

essential to mention muscular tissue and ROS formation in any discussion of the effects of

aerobic exercise on atherosclerosis. The various components of muscle fibres that produce these

reactive biomolecules include the mitochondria, sarcoplasmic reticulum, transverse tubules,

sarcolemma, and the cytosol (56). This is noteworthy because aerobic exercise, which is


commonly used to treat or prevent pathological conditions, also leads to the generation of

reactive molecules.

It is well known that ROS are very significant biomolecules since they are produced

throughout the body. A common misconception, however, is that ROS are primarily responsible

for only pathological developments. In fact, they have very important physiological, as well as,

pathological effect on a variety of biochemical processes (See Figure 3). Specifically, ROS play

a very important role in cellular signaling through redox status, which can lead to cellular

apoptosis (10) and the synthesis or folding of proteins. ROS are also involved in the regulation of

the structure and activity of enzymes, receptors and transcription factors (8, 22).

With respect to vascular function, ROS can operate like second messengers through the

mediation of the production of prostaglandins (30). Prostaglandins are responsible for

constricting and dilating vascular smooth muscle cells (VSMC), platelet aggregation and

disaggregation, and the regulation of inflammatory processes. In terms of vascular pathology,

ROS can lead to the production of adhesion molecules, lipid oxidation, as well as, altered

vasomotion (71).

There are a number of metabolic and cardiovascular disorders that are associated with the

production of ROS including hypercholesterolemia, hypertension and diabetes (47). An

alteration in the concentration of ROS can lead to several vascular diseases including

atherosclerosis (39). With an increase in the production of ROS in vascular endothelial cells,

there is a subsequent increase in the oxidation of LDL-C, inflammatory cytokines, adhesion

molecules, and monocyte infiltration of vascular endothelium (24). These processes are all

associated risk factors that further development and increase the severity of atherosclerosis. This

provides ample reason to examine the effects of ROS on vascular endothelial function.


ROS and Vascular Endothelial Function

As previously discussed, ROS are essential for producing alterations in vascular

endothelial tissue. This is significant because the control of vascular function is fundamental for

many physiological processes including oxygen, nutrient, and hormone transportation, as well as

waste removal, thermoregulation, blood pressure regulation, etc. Specifically, ROS have been

shown to have important signaling functions that can cause alterations in vascular tone and lead

to endothelial cell growth and remodeling. (15, Also see figure 4).

One of these alterations, vasomotion (the ability of VSMC to constrict and dilate), can be

controlled through changes in redox status. Variations in ROS concentrations, which alters redox

status, directly affects the expression of NO, the most important vasodilator expressed in

vascular endothelial cells (20). H2O2, one of the more stable reactive species, facilitates NO

synthesis by increasing eNOS activity (43). O2.-, on the other hand, reacts negatively with NO,

causing it to lose its ability to cause endothelium-dependent vasodilation. (43). This alteration in

NO availability, is the primary mechanism contributing to the impairment of endothelium-

dependent dilation (73).

The regulation of blood flow by ROS is not only very important for controlling

endothelial function but it also plays a vital role in the expression of inflammatory cytokines and

adhesion molecules. Through changes in redox status, ROS can cause an increase in the

production of TNF-α and IL-6, which leads to an increase in VCAM-1 and monocyte

chemotactic protein-1 (MCP-1) (43). The alterations that take place in the vascular endothelial

cells following the inflammatory process are crucial in the initial development of many vascular

diseases (24).


Following damage to the endothelium, VSMC will also produce vascular adhesion

molecules (39). These adhesion molecules, in turn, lead to the generation of additional ROS,

furthering the expression of inflammatory cytokines and supplementary adhesion molecules.

Functionally, vascular adhesion cells initiate the attachment of leukocytes to the endothelium (3).

This response while fundamental for a number of normal biological processes can, however, also

lead to pathological conditions.

It is clear that elevated levels of ROS lead to an increase in many of the signs of

endothelial dysfunction, and can ultimately progress to the development of atherosclerosis. One

study conducted by Tribble et al demonstrated that there is a direct relationship between

superoxide dismutase (SOD) activity and atherosclerotic lesion formation in mice (75). These

results advance the connection between ROS and endothelial dysfunction in atherosclerosis.

ROS and Low-Density Lipoprotein Cholesterol (LDL-C)

ROS alter the function of many tissues by reacting with other biomolecules. One

biomolecule in particular, LDL-C, has been shown to have significant deleterious effects on the

progression of CVD when found in elevated blood concentrations (33). This negative effect is

increased by the interaction of LDL-C with ROS, further heightening the risk of developing

CVD. Lipoproteins such as LDL-C, however, are very important for normal biological functions.

Their primary role is to transport cholesterol and TG from the liver to peripheral tissues.

Cholesterol is an essential component of human cell membranes; is a precursor for steroid

hormone synthesis (51); and activates membrane bound enzymes, receptors, and ion channels

(14). TGs also have a number of important functions, the most common of which is for energy

production through oxidative metabolism. Therefore, it is apparent that lipoproteins make an

important contribution to the structure and function of tissues throughout the body.


Modified forms of LDL-C, specifically OxLDL, are more proatherogenic than native

forms of LDL-C (25). Non-oxidized or unaltered LDL-C has been shown to have little or no

effect on ROS formation (23). The oxidative process that takes place forming OxLDL leads to

the formation of less stable biomolecules including lysophosphatidylcholine (LPC) and

aldehydic lipid peroxidation products. LPC in particular, increases the synthesis of NAD(P)H-

oxidase, one of the major enzymes responsible for ROS generation (23). The oxidation of LDL,

not only directly affects its normal function, but also leads to an increase in the formation of

ROS. This increases the oxidization susceptibility of additional LDL particles.

OxLDL is not only responsible for increasing ROS formation, but is also a major

contributor to vascular endothelial dysfunction. OxLDL has been shown to be cytotoxic to both

endothelial and smooth muscle cells within the vasculature (31). As previously mentioned, NO is

one of the major facilitators of vasodilation. One of the reactions that takes place as a result of

LDL oxidation, is the dissociation of eNOS. This alteration leads to an increase in the production

of eNOS derived O2.- (21). Thus, OxLDL can further ROS formation, as well as, induce

vasoconstriction by limiting NO availability (41).

OxLDL induced changes in endothelial function are very important when considering the

initial development of atherosclerosis. There are, however, direct implications associated with

OxLDL formation and atherogenesis. OxLDL causes the expression of adhesion molecules (70),

which leads to the initial binding of macrophages to the arterial wall and their ultimate

infiltration through the fenestrations in the endothelial tissue. Higher levels of LDL oxidation

have also been shown to increase the concentrations of macrophage-rich plaques. These

modified macrophages lead to plaque instability (49), which magnifies the risk of developing a

stroke or heart attack.


The chronic inflammatory process that takes place during atherogenesis is not only

furthered by the oxidation of LDL-C, but also is itself, a major contributor to OxLDL formation.

Changes in LDL-C concentration, size, and susceptibility to oxidation have been observed during

the inflammatory process (16). In a study performed by Memon et al, additional evidence has

been documented which demonstrates that LDL oxidation takes place during both an infectious

and inflammatory state (46). Elevated levels of both non-altered LDL-C and oxidized LDL-C

correlate with the incidence of atherosclerosis (26), implicating their role in the development of

CVD.

Aerobic Exercise on Redox Status and Endothelial Function

Currently, there are a variety of methods that are used to treat and prevent CVD. Regular

exercise has been shown to have a significant impact in the prevention of many CVDs. This is a

result of the fact that it improves the serum lipid profile, increases insulin sensitivity, and lowers

blood pressure (BP) (7, 2). Following a single session of moderate intensity aerobic exercise

(70% VO2max), there is a significant decrease in both LDL-C and TG, as well as, a subsequent

increase in HDL-C (19). In fact, HDL-C concentrations, which are inversely related in the risk of

developing many CVDs, have been shown to increase by up to 21% following a single bout of

exercise (19). Studies performed by Powell et al and Sanchez-Quesada et al confirm that HDL-C

levels increase for several days following a single bout of exercise, while at the same time

lowering plasma TG concentrations (53, 64). These results are significant because HDL-C has

been shown to protect LDL from oxidative changes (40).

It is evident that aerobic exercise plays a preventative role in the development of CVD,

however, it is also one of the primary contributors to ROS formation. The contraction of skeletal

muscle fibres can lead to the generation of ROS through a number of different pathways. The


predominant source of free radical formation during exercise is from the electron transport chain

within the mitochondria (12, 57). With increasing levels of exercise intensity, O2 consumption

can increase up to ten times resting levels (35). As previously discussed, O2 is a major source of

ROS generation (13). Strenuous physical activity is associated with an increase in oxidative

stress via lipid peroxidation (37), followed by elevated levels of tissue damage (27). Contrary to

the pervious findings, Shi et al found that there was no significant increase in oxidative stress

following either aerobic or anaerobic exercise (69).

Exercising muscles lead to the formation of ROS, however, they also contain a network

of antioxidant defense mechanisms that reduce the risk of oxidative damage. For instance,

muscle fibres contain both enzymatic and nonenzymatic antioxidants to regulate redox status.

Common enzymatic antioxidants include SOD, glutathione peroxidase (GPX), and catalase

(CAT). SOD activity can be modified by changes in physical activity levels. While the results

from some studies dispute the dynamic properties of SOD (5, 29), most studies have shown

significant increases of this antioxidant from 20% up to 117% (11, 54, 55, 58). GPX and CAT

have also been shown to be elevated in highly active muscle fibres (11, 29, 58).

The two major forms of nonenzymatic antioxidants include glutathione (GSH) and

coenzyme Q10 (Ubiquinone). GSH is the most important nonenzymatic antioxidant in muscle

tissue, and similarly to the enzymatic antioxidants, has been shown to increase in concentration

following aerobic exercise (57). GSH functions as an antioxidant by acting as a proton donor, as

well as, by serving as a substrate for GPX to eliminate H2O2 (57). Coenzyme Q10, acts by

scavenging RO2.- radicals, thereby inhibiting lipid peroxidation (57). Therefore, it is clear that

while exercise may increase the concentrations of pro-oxidants (ROS), it also increases anti-

oxidant concentrations to combat oxidative stress.


Biochemical changes are not the only alterations that occur as a result of aerobic exercise

training. The shear stress that is caused by the increase in blood flow and blood pressure during

exercise has a positive effect on endothelium-dependent dilator-function (34, 67). Chronic

exercise produces a more long lasting increase in endothelium-dependent dilation, predominantly

as a result of an increase in NO synthesis (50). In another study, Kingwell et al found that there

was a greater vasodilating response to acetylcholine (ACh) in trained individuals compared to

untrained individuals (38, 66). Following a 12-week exercise program, Higashi et al

demonstrated that there was not only an increase in vasodilating response to ACh, but also in the

synthesis of NO, along with positive functional and histological alterations in vascular

endothelium (32).

Additional significant findings with respect to aerobic exercise on endothelial function

include a reduction in the expression of MCP-1 and lowered plasma concentrations of adhesion

molecules (82). These results indicate, that not only does aerobic exercise lead to beneficial

vasodilating responses, but it also prevents monocytes from adhering to the vascular

endothelium. This is noteworthy because these alterations act to prevent the initial formation of

atherogenic lesions.

Effects of Aerobic Exercise on LDL Oxidation

The oxidative modification of lipoproteins has a fundamental role in the initial

development of atherosclerosis. By limiting the availability of LDL particles or by decreasing

their susceptibility to oxidation, it is possible to decrease the incidence of endothelial damage,

thereby preventing the formation of atherogenic lesions. One of the enzymes responsible for

lipoprotein metabolism, lipoprotein lipase (LPL), can be influenced by aerobic exercise. In fact,

LPL plasma levels are elevated in trained individuals when compared to untrained individuals


(78, 65). Following a 10-month exercise program, this change in lipoprotein metabolism lead to

a 10% decrease in LDL-C in men and a 11% decrease in women (76). The significance of this

finding is that reducing the presence of LDL-C through aerobic exercise training is a promising

approach to preventing its availability for oxidation and the resulting endothelial damage.

Some studies have shown that, with exercise, LDL-C plasma concentrations are similar in

both active and sedentary individuals, however, the susceptibility to oxidation of these

lipoproteins is very different. For example, subjects with a high endurance level have been

shown to be more resistant to in vitro LDL oxidation (64, 68). In contrast, a number of studies

have shown that LDL susceptibility to oxidation greatly increases following an acute bout of

exercise (62, 63, 79). To recall, O2 consumption can increase by up to ten times normal resting

levels during exercise (35). Since O2 is a major source of ROS formation, a common

misconception is that free radical concentrations will increase as a result of exercise. From this

may develop the assumption that the susceptibility of LDL to oxidation may well increase

because of elevated ROS formation. However, it is important to remember that aerobic exercise

also increases antioxidant levels, which helps to maintain the balance in redox status, preventing

oxidative stress.

It has been speculated that oxidative stress leading to LDL oxidation is dependent on the

duration and intensity of an exercise session. The assumption is that with higher levels of

intensity or longer durations of exercise, there is a greater risk of LDL susceptibility to oxidation.

Kaikkonen et al investigated the effects of a marathon run in both men and women. They found

that following exercise of extreme duration, lipid oxidation susceptibility decreased by 24.8%

and antioxidant levels increased by 14.6% (36).


Another study that analyzed the effect of a short-term maximal exercise, discovered that

there was no change in lipid peroxidation (13). These results explain that the antioxidant capacity

in most individuals is adequate protection against oxidative changes.

Aerobic exercise has also been shown to have a significant effect on OxLDL mediated

inflammation. A study performed by Wang et al demonstrated that exercise lead to OxLDL

induced platelet aggregation (77). This effect was also demonstrated by Tozzi-Ciancarelli et al

immediately following a single session of aerobic exercise (74). In the same group, however,

following a 20-week program, these oxidative modifications decreased, suggesting that a regular

exercise program is optimal for reducing OxLDL concentrations.

Aerobic Exercise and Atherosclerosis

It is obvious and noteworthy that there remains conflicting information about the effect of

aerobic exercise on oxidative stress. Some studies explain that aerobic exercise leads to an

increase in oxidative stress, thereby increasing the risk factors associated with atherosclerosis. In

contrast, there are a number of other studies suggesting that aerobic exercise increases ROS

formation, yet go on to explain that the subsequent increase in plasma antioxidants prevents

oxidative stress.

Roberts et al performed a study that examined the effects of lifestyle modifications on the

major contributing factors associated with atherogenesis. In a group of men, all with metabolic

syndrome, lifestyle changes were shown to improve lipid and metabolic profile; decrease

inflammation and monocyte adhesion; and decrease endothelial cell and platelet activation (61).

The lifestyle changes of note included both an increase in physical activity levels and dietary

modifications. It is important to note the significance of dietary modifications as they also play

an important role in many metabolic, as well as, cardiovascular diseases.


It is commonly understood that aerobic exercise acts as a protective factor against the

development of atherosclerosis. The association between physical fitness and the prevalence of

atherosclerosis goes beyond simply noting the specific biomarkers associated with the

development of the disease. Rauramaa et al found that there is an inverse relationship between

cardiorespiratory fitness and carotid atherosclerosis (60). A separate study conducted by

Ramachandraa demonstrated that exercise could reduce the presence of pre-existing aortic

atherosclerotic lesions (59).

These results are quite significant because they make it clear that exercise will not only

prevent atherogenesis, but also provide a mechanism to the treatment of those individuals with

the disease. Equally important is that some studies have shown that there is an association

between inactivity and low-grade systemic inflammation in healthy individuals (1, 18). This

suggests that physical inactivity may actually lead to an increase in the risk of developing

atherosclerosis.

Conclusion

It is well known that oxidative stress plays a very important role in many pathological

conditions. It has also been shown that the formation of ROS is one of the most significant

contributing factors in the development of atherosclerosis. This leads to what would seem to be a

counterintuitive situation. Aerobic exercise, which is the most common preventative treatment

for atherosclerosis and many other diseases, is also a major source of ROS generation.

There are many studies that suggest that the increase in free radical formation, resulting

from exercise, will lead to oxidative stress resulting in an increase in the susceptibility of LDL to

oxidation. However, there is a significant amount of research that demonstrates that aerobic

exercise, of various intensities and durations, leads to the production of a variety of antioxidants.


In order to further clarify the exact role of exercise with respect to changes in oxidative

stress, it is necessary to refine what is truly meant by the term oxidative stress. It is clear that

exercise induced ROS formation is controlled, since it has been shown that aerobic exercise does

indeed successfully prevent and reverse the signs of atherosclerosis.


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Appendix

Figure 1 – An illustration comparing normal endothelial function with endothelial dysfunction (48).

Figure 2 – Changes in OxLDL and endothelial function seen in the progression of atherosclerosis (48).


Figure 3 – The physiological and pathological contributions of ROS (43).

Figure 4 – The presence of ROS and signs of endothelial dysfunction (71).

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Exercise on OxLDL and Atherosclerosis