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1. Introduction
O2 arose on Earth in about 3.8 x 109 years ago due to the photosynthetic process in
cyanobacteria hydrolyzed water. But it was only about 2.5 x 109 years ago that its levels rose to
significant amounts. The increase in atmospheric concentrations of O2 led to a great selective
event, the first great mass extinction, due to stress on organisms that did not adapt to the new
conditions. It also helped in the conquest of the land with the formation of O3 (ozone) in the
stratosphere, which filters the most harmful of the ultraviolet radiation (UV-C). In addition,
using the O2 as a substrate, the organisms generated much more energy (about 32 times more)
but, in doing so, they started to generate reactive species in the process.
Reactive species (RS) are elements that react with biologically relevant organisms and
although they act as cellular messengers, they also damage cellular components. In response to
that, the organisms developed defences, which are now called antioxidants. The imbalance of
the relation between RS and antioxidants is called oxidative stress. In this chapter we will
study diseases related to oxidative stress but, in order to understand them, we first need to
comprehend the radicals, their chemistry and the defences against such elements.
1.1 Reactive oxygen species (ROS) and reactive nitrogen species (RNS)
The RS are named according to the principal element in their composition, reactive oxygen
species (ROS) and reactive nitrogen species (RNS), and are divided into radicals and non-
radicals. Radicals have at least one unpaired electron in an open shell configuration and
non-radicals are compounds that can generate radical species. Below we will see a list of the
most important reactive species for human health (considered to date).
Note: Radicals are written with a dot attached to the upper right level representing the
unpaired electron.
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4 Coronary Artery Diseases
It can be formed mainly by the Fenton reaction, in which the hydrogen peroxide (see below)
reacts with a transition metal (Fe2+ or Cu+) forming two hydroxides, one of them a radical
and the other just an ion (see equation below).
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Coronary Artery Disease and Oxidative Stress 5
1.2.1 Enzymatic
Catalase
Catalase is a very reactive enzyme that dismutates hydrogen peroxide (H2O2) into water
(H2O) and O2, as seen in eq. 3.
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6 Coronary Artery Diseases
The MnSOD (SOD2) is quite different from CuZnSOD (not even having similar amino acid
sequences), but performs the same reaction. It is more sensitive to denaturation (e.g. by heat)
than the CuZnSOD. Each of its four protein subunits contains a manganese ion.
Heme + 3O2 + 3½NADPH + 3½H+ + 7e- → biliverdin + Fe2+ + CO + 3½NADP+ + H2O (12)
The biliverdin reductase acts on biliverdin by reducing its double-bond between the pyrrole
rings into a single-bond with NADPH+H+ generating then, biliverdin and NADP+. The
biliverdin then takes on antioxidant properties by scavenging peroxyl radicals and limiting
the peroxidation of membrane lipids and proteins.
1.2.2 Non-enzymatic
Glutathione
Glutathione (GSH) is a tripeptide, the most ubiquitous peptide found in cells. GSH can be
obtained from the diet or can be synthesized de novo in the liver. It is the most abundant
intracellular antioxidant. It works as a cofactor to GPx (as seen above) and also reacts, in
vitro, with HO•, ONOO- among others species. It can also chelate copper, reducing its
interaction with hydrogen peroxide, decreasing the Fenton reaction, and therefore reducing
the formation of HO•. Its reaction with ONOO- leads to the formation of nitrosothiol
(GSNO) which can be converted to NO•.
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8 Coronary Artery Diseases
micronutrient or a catalyst of free radical reactions. The average human adult contains
approximately 4 g of iron, a little more than 2 g of which is in hemoglobin and 1g in body
stores predominantly in the liver, the rest are in other iron-containing proteins, mainly in
skeletal muscle (~300mg, most in myoglonbin) and macrophages (~600mg in total). Since
total plasma iron turnover is some 35mg/day, iron deficiency can cause cellular growth
arrest and death; iron excess can cause damage lipid membranes, proteins and nucleic acids.
For example, iron deficiency represents the most common cause of anaemia worldwide and
can cause development retardation in children as iron overload in hereditary
hemochromatosis and thalassemias leads to potentially fatal liver or heart failure due, in the
most part, to the amount of iron deposits.
Iron absorption needs to be tightly controlled due its activity redox which can also lead to
the production of ROS. Its absorption occurs in the proximal small intestine and involves
many key molecules. Iron absorption occurs in lumen of the duodenum and can be
modulated by the size of the body’s iron stores, by erythropoietic activity and by recent
dietary iron intake. Iron can be absorbed from diet in two forms: as inorganic (non-heme)
iron predominantly released from foods such as vegetables or cereals, or as heme iron from
the breakdown of hemoglobin and myoglobin contained in red meat. Most iron in food is in
ferric form [Fe (III) state], the most stable oxidation state for iron. Iron across is mediated by
brush border iron transporter divalent metal transporter 1 (DMT1), which transports iron in
the ferrous form [Fe (II))]. Hence, there are agents in gastric juice that solubilize and reduce
Fe (III) in Fe (II), such as the ascorbate and hydrochloric acid (Frazer & Anderson, 2005),
moreover, there are also in the epithelial surface apical ferric reductases. Heme
(protoporphyrin ring that binds ferrous form) is more efficiently absorbed than inorganic
iron and taken up by apical heme transporters after being released by proteolysis of
hemeproteins in gut lumen is taken up and the iron removed from it in the mucosal cells by
the action of heme oxygenase in ferrous form (Figure 1).
Inside the enterocytes, iron can be stored in ferritin in the cytoplasm, utilized in
mitochondria or exported to plasma by ferroportin on the basolateral surface. Ferroportin
cooperates with the multicopper ferroxidase hephaestin, which converts ferrous to ferric
iron for uptake by plasma transferrin and regulated by hepcidin, an inhibitor of iron
absorption and releases from macrophages and other cell types. The hepcidin causes
ferroportin internalization and degradation, decreasing the transfer of iron to the body.
Extracellular iron is bound with high affinity by the serum iron-transport protein transferrin
and taken into the circulation (the labile iron pool). The majority of it is destined for nascent
erythrocytes in the bone marrow. The cellular uptake of iron occurs through receptor-
mediated endocytosis of transferrin (TfR). TfR containing transferrin binds on the cell
membrane and is internalized by endocytosis. So, iron is used for cellular processes and
excess iron is stored in ferritin (Dunn et al., 2007). It is important to know about these
proteins because they have key roles in healthy processes and diseases in relation to iron
homeostasis, for example, formation of atherosclerotic lesions, as will be discussed later. The
excess of iron is lost by epithelial shedding in the gastrointestinal tract and the skin
(approximately 1 to 2 g each day), through blood loss in menses of premenopausal women,
in sweat and possibly a small amount excreted by lungs into mucus. The amount of iron
absorbed can be affected by several mechanisms like inflammation, hypoxia, anaemia and
iron overload. Iron can be recycled or stored as needed. Human erythrocytes undergo
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Coronary Artery Disease and Oxidative Stress 9
surface alterations that mark them to be phagocyted and digested by macrophages in the
spleen and the liver. In macrophages, iron is recovered from heme by the action of heme
oxygenase and stored in ferritin, but the major site of iron storage is the liver, into
hepatocytes. The capacity of readily exchanging electrons makes iron not only essential for
fundamental cell functions, but also a potential catalyst for chemical reactions involving
free-radical formation and subsequent oxidative stress and cell damage. Therefore, iron
levels are carefully regulated to minimize the pool of potentially toxic “free iron”. The
majority of proteins described above are posttranscriptional controlled by iron regulatory
proteins (IRP-1 and IRP-2). Iron regulatory proteins recognize at the mRNA level non-
coding sequences (the iron-responsive elements [IRE]) which have been found in genes that
control the iron homeostasis like ferritin and TfR, being that the ferritin synthesis is
increased to sequester excess iron and TfR is downregulated in order to stop iron uptake
(Cairo & Pietrangelo, 2000).
Fig. 1. Intestinal iron absorption. Iron absorption in the proximal small intestine mucosa of
the gut requires transport across the apical and basolateral membranes of duodenal
enterocytes. The dietary non-heme iron in the duodenal lumen is reduced by a ferric
reductases and thus made available for divalent metal transporter 1 (DMT1), which
transports ferrous iron across the apical brush border membrane and heme iron is
transported by heme transporters. The amount of iron not retained by the cell inside the iron
storage protein ferritin (Ft) is transferred to the bloodstream. The basolateral release of non-
heme iron (which is also derived from heme catabolized by heme oxygenase [HO]) is
mediated by ferroportin (FPN) which transports the metal across the membrane and
hephaestin (Hp), which re-oxidizes iron as a necessary step for binding to the plasma carrier
protein transferrin (Tf). The hepcidin causes ferroportin internalization and degradation,
decreasing the transfer of iron to the body. The main proteins involved in iron absorption
are controlled by iron regulatory proteins (IRPs), whose activity is regulated by the levels of
the metal in the labile iron pool.
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Coronary Artery Disease and Oxidative Stress 11
vivo is the metal-catalyzed protein oxidation pathway. In addition, there are others modes of
inducing protein oxidation, among them are oxidation induced cleavage, amino acid
oxidation and the conjugation of lipid peroxidation products. It is important to know that
the accumulation of oxidized proteins is often measured by the content of reactive
carbonyls. Some protein damage is reversible, such as methionine sulphoxide formation and
destruction of Fe-S clusters by O2•-. Other damage, for example of side-chains to carbonyl
residues, appears irreversible and the protein is destroyed and replaced. Several
mechanisms are activated when a protein undergoes damage by reactive species. This is
necessary because accumulation of proteins with incorrect conformation can lead to cell
death. When oxidized proteins resist proteolytic attack, they form aggregates which
decrease their toxicity by sequestering them in insoluble clumps (Halliwell & Gutteridge,
2007).
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12 Coronary Artery Diseases
Carbon radicals often stabilize by molecular rearrangement to form conjugated dienes, but if
two radicals collide within a membrane they cross-link the fatty acid side-chain. When the
formation of peroxy radical (by O2 action) occurs, this can abstract a hydrogen atom from an
adjacent fatty-acid side-chain. Thus happen the propagation stage of lipid peroxidation,
mainly in membranes.
2. Atherosclerosis
Cardiovascular diseases are the leading cause of death and disability in the Western world.
The majority of cardiovascular diseases result from complications of atherosclerosis.
Atherosclerosis is a progressive disease that is generally characterized by the accumulation
of lipids, fibrous elements and inflammatory cells and molecules within the arterial wall.
The lesions of atherosclerosis occur principally in large and medium-sized elastic and
muscular arteries and can lead to ischemia of heart, brain or extremities, resulting in
infarction.
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Coronary Artery Disease and Oxidative Stress 13
promote atherosclerosis. LDL retained within the artery can be oxidized by a number of cell
types present within arteries, including endothelial cells, smooth muscle cells, monocytes
and macrophages, and lymphocytes. HDL can also be oxidized by endothelial cells and by
chemical means. Oxidation of these lipoproteins can be blocked by antioxidants. Ox-LDL
also has potentially atherogenic affects, inhibits the mobility of tissue macrophages,
enhances production of chemotatic factors and adhesion molecules, induces smooth muscle
cells’ migration and both proliferation and apoptosis in endothelial cells, smooth muscle
cells and macrophages (Schwenke, 1998). In the vasculature, production of reactive species
occurs that are used to control physiological functions. Oxygen undergoes reduction to O2•-
by means of enzymes, such as the nicotinamine adenine dinucleotide (phosphate)
(NADH/NAD(P)H) oxidases and xantine oxidases (XO). The O2•- is used to promote
vasoconstriction and can form H2O2 that can react with other radicals, such as transition
metal Fe2+ to produce OH• (Fenton reaction). Myeloperoxidase, a heme protein secreted by
phagocytes, can amplify the oxidative potential of H2O2 by production of hypoclorous acid
(HOCl) that can react with O2•- to produce OH•. Other sources of ROS in the vessel wall
include mitochondria, ciclooxygenase (COX), lipoxygenase and uncoupled endothelial nitric
oxide synthase (eNOS). This last, in normal conditions, generates nitric oxide (NO•), but if
there is availability of precursors, eNOS become uncoupled generating O2•-. Although NO•
is a reactive species, it is thought be antiatherosclerotic because it is a vasodilator potent and
inhibits LDL peroxidation by scavenging peroxil radicals. These reactive species (O2•- , H2O2
and NO•) cannot oxidize LDL, but form other reactive species that can do this, like OH• and
ONOO- (described above) (Madamanchi et al., 2005, Halliwell & Gutteridge, 2007). But how
can free ferrous iron in the body be a catalyst for the formation of OH•, powerful pro-
oxidants and promote lipid oxidation (increased formation of ox-LDL)? In 1981 Sullivan
created The Iron Heart Hypothesis suggesting that increased body iron stores are a risk
factor for coronary heart disease and thus that iron depletion though phlebotomy or other
means can reduce risk (Sullivan, 1981). In addition to enhancing oxidative stress, increased
iron stores are believed to adversely affect cardiovascular disease through other
mechanisms, including alteration of endothelial function, decreased vascular reactivity and
reperfusion injury by iron-induced free radicals (Hu, 2007). Furthermore, iron can contribute
to the signalling in inflammatory pathways and hypoxia response. Atherosclerosis is an
inflammatory disease and inflammatory mechanisms have emerged as playing a pivotal
role in all stages of atherosclerotic plaque formation. Systemic inflammation occurs in the
vasculature as a response to injury, lipid peroxidation and perhaps infection. A number of
inflammatory mediators are released by cells involved in the lesion, including tumour
necrosis factor α (TNFα) or interleukin 1 (IL-1), chemokines, such as IL-8 or monocyte
chemoattractant protein-1 and adhesion molecules, such as intercellular adhesion molecule
1 (ICAM-1) or selectins. In particular, smooth muscle cells also release IL-6 which is the
main hepatic stimulus for the acute phase reactant, C-reactive protein (CRP), which causes
expression of adhesion molecules and also stimulates hepcidin. The ferritin also has
synthesis regulated by cytokines, such as TNFα and IL-1, at various levels (transcriptional,
posttranscriptional and translational) (You & Wang, 2005).
Abnormal ferritin levels or iron homeostasis have been linked to atherosclerosis. To prove
the iron hypothesis, many epidemiological studies have been performed. Most studies
testing the hypothesis of iron measured levels of ferritin. The ferritin level rises with iron
loading and declines with depletion of tissue iron stores. Salonen et al. first reported a
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14 Coronary Artery Diseases
significant association between the serum ferritin levels and the risk of myocardial infarction
of 1,931 middle-aged men during an average follow-up of three years (2.2 higher risk of
myocardial infarction in men with higher serum ferritin levels) (Salonen et al., 1992). A
study from our laboratory compared patients with coronary heart disease and sleep apnea
(also inflammation disease) showing that serum ferritin levels increased in coronary heart
disease patients and positively correlated with sleep apnea. These studies are supported by
the evidences that show iron deposition in human atherosclerotic lesions, suggesting that
iron may play a role in the development of atherosclerosis (Hower et al., 2009).
With regard to sleep apnea, studies have demonstrated sleep disordered breathing to be
associated with cardiovascular disease, include coronary artery disease, heart failure,
hypertension, cardiac arrhythmias and stroke, which further increase morbidity and
mortality in the sleep disordered breathing population (Flemons et al., 1999). Hypoxia
events, endothelial dysfunction, coagulopathy, impaired sympathetic drive, oxidative and
inflammatory stress are the pathophysiological pathways suggested for the development of
cardiovascular disease in sleep disordered breathing (Butt et al., 2010). Increase in ROS in
endothelial cells exposed to hypoxia has been evidenced. Among the possible sources of
ROS by hypoxia are the mitochondria, leukocytes (NADPH oxidase pathway) and epithelial
tissue enzymes, such as xanthine oxidase, cyclooxygenase, lipooxygenase, NO-synthase and
hemeoxygenases (Lavie, 2003). As discussed above, hepcidin is a peptide also involved in
iron homeostasis and has impact in inflammatory hypoferrimia because inflammation is
mediated by citokine-driven increase in hepcidin production, causing release and recycled
iron from macrophages and and blocking the passage of iron from enterocytes to plasma.
Hepcidin production is controlled by inflammatory citokines like ferritin. The main
citokines are IL-6 and TNFα. In addition to cytokines, hepcidin is downregulated under
hypoxia conditions and little is known of the involvement of ROS in this mechanism. A
study suggested that ROS (produced by hypoxia) repress the hepcidin gene (Choi et al.,
2007).
The same recent study in our lab that verified the serum ferritin levels in coronary heart
disease (CHD) and sleep apnea patients also verified the serum prohepcidin levels (the
precursor of hepcidin). The study was performed in 56 patients with stable coronary heart
disease referred for angiography (male gender 54%). Exclusion criteria, to avoid potent
oxidative stress factors, were: smoking, age older than 65 years, morbid obesity, diabetes.
Patients underwent a portable polysomnography to verify the apnea-hypopnea index (AHI)
and determination of hemoglobin, hematocrit, ferritin, prohepcidin and high-sensitivity C-
reactive protein (hs-CRP) levels. Patients were divided into controls and cases at the median
AHI, 28 controls with an AHI low and 28 cases with moderate to severe AHI. The mean
ferritin levels are significantly higher in cases than the control and this is the first report of
such findings in sleep apnea (170±140.1 vs. 285±194.5; p < 0.05). There were a significantly
greater percentage of subjects with CHD in the group with moderate to severe sleep apnea
(72%; p 0.001). The Pearson’s correlation coefficients showed positive significance between
ferritin and AHI (r = 0.398, P = 0.002), prohepcidin and ferritin (r = 0.432, P = 0.001) and iron
and ferritin (r = 0.346; P = 0.009); between AHI and prohepicidin was r= -0.15 (P = 0.3)
(figure 2). How hypoxia could be affecting the ferritin and hepcidin levels is not known. In a
multivariate regression, however, controlling for age, sex, body mass index and coronary
heart disease, the AHI and ferritin explain 30.4% of the variance of prohepcidin. Thus, it is
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Coronary Artery Disease and Oxidative Stress 15
Fig. 2. Scheme of regressions and correlations found among studied parameters. The sleep
apnea through intermittent hypoxia (IH) events activates some unknown route (?)
generating decreased prohepcidin levels and increased ferritin levels. The hypoxia interferes
positively in the ferritin levels and negatively in prohepcidin levels. Prohepcidin already
induces the ferritin synthesis. It is suggested that the hypoxia induction by ferritin levels
overlaps the prohepcidin inhibition by hypoxia, because there was increased ferritin levels,
as well as increased AHI. A relationship was found between OSAS and CHD, as well as
ferritin and CHD corroborating with literature data.
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16 Coronary Artery Diseases
The 8-OHdG is typical biomarker of oxidative stress. Increased 8-OHdG levels are
frequently related to cardiovascular disease. The level of 8-OHdG has been demonstrated to
be very high in aorta fragments taken at surgery from patients suffering from severe
atherosclerosis lesion. An increase 8-OHdG levels in DNA isolated from lymphocytes are
related to cardiovascular disease (Gackowski et al., 2001).
3. Hypercholesterolemia
Cardiovascular disease is a complex and multifactorial disease; there can be no doubt now
that elevated plasma cholesterol levels play a dominant role. Hypercholesterolemia is
associated with an increased risk of atherosclerosis. Fatty streaks can even be found in the
foetus, to an extent increasing with maternal plasma cholesterol levels. There are genetic
disorders that may have a relationship with hypercholesterolemia, such as a disease familial
hypercholesterolemia, in which the LDL receptors are defective or absent, so that blood LDL
(and hence cholesterol) levels become very high and these people have high atherosclerosis
incidence (Halliwell & Gutteridge, 2007).
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Coronary Artery Disease and Oxidative Stress 17
2010). In addition, the residual oxidized phospholipid containing aldehyde terminate fatty
acids. These, and presumably many other changes, generate immunogenic neo-epitopes on
the modified LDL and are important to the atherosclerotic process. A variety of oxidized
lipids’ products, with similar characteristics of ox-LDL, are found in human plasma,
atherosclerotic tissue and urine. Although some of these may indeed arise from oxidation of
LDL, they could equally derive from oxidation of lipids at other sites and that oxidation
may or may not parallel the rate at which LDL itself is undergoing oxidative modification
(Witztum & Steinberg, 2001). Some of these proatherogenic effects of ox-LDL could also be
induced by organic phase extracts of ox-LDL, suggesting that oxidized lipids themselves
were proatherogenics, in addition to oxidatively modified ApoB (Davies & Roberts, 2011).
Still addressing LDL, it can be oxidized non-enzymatically by transition metal ions, heme
and other catalysis. On the other hand, there are many postulated mechanisms by which
LDL could become oxidized via several enzymes within the artery wall. Transitions metals
are important to lipid oxidation. Most cells present in the arterial intima can promote LDL
oxidation by its enzymes that mediated LDL oxidation, but it arguably requires the presence
of transitions metals, iron or copper microconcentration. Elevated levels of metal ions are
present in the advanced atherosclerotic lesions. Tissue homogenates prepared from
atherosclerotic lesions contain catalytically active metal ions, indicating that these metals
may stimulate LDL oxidation in the artery wall. One mechanism that has now gained strong
support is the enzimatic. Lypoxygenase is one intracellular enzyme that directly oxygenates
polyunsaturated fatty acids. The enzyme initiates the seeding of LDL with hydroperoxides,
leading to the subsequent initiation of lipid peroxidation. These lipid peroxides could be
released from cells and might translocate to LDL. Leucocytes-released myeloperoxidase
catalyzes the formation of reactive substance species (HOCl) and generates a series of
secondary radical or non-radical oxidants that may provide lipid peroxidation, oxidized
LDL, advanced glycation end products and nitrating species. Among the mechanisms
protein glycation is included. The last mechanism cited refers to NO• (which has already
been mentioned here). Although NO• is a stable radical that fails to oxidized LDL at
physiological pH, it is rapidly inactivated by O2•- to form peroxynitrite, a potent oxidant,
implicating in LDL oxidation. This mechanism should be important in vivo since endothelial
cells, smooth muscle cells and macrophages generate O2•- (Yoshida & Kisugi, 2010). There
are lipid peroxidation products in the vasculature that do not arise directly from LDL and
could contribute to atherogenesis. These oxidation products create proinflammatory
mediators that drive a chronic inflammatory state, such as isoprostanes. It is important to
know that well-established risk factors as causes of cardiovascular disease may have lipid
peroxidation as part of its mechanism, such as smoking and diabetes (Davies and Roberts,
2011). Therefore, the evidence shows us clearly that hypercholesterolemia plus other risk
factors increase the disease process and progression.
The oxidant hypothesis makes us question whether or not administration of antioxidants
significantly slows the formation of atherosclerotic lesion. In a large number of
epidemiologic studies, the dietary intake or plasma levels of antioxidant nutrients correlates
negatively with risk of clinical cardiovascular disease. The user in clinical trials is
tocopherols and beta-carotene because they are naturally occurring nutrients which would
pose no toxicological problems. The relevance of vitamin C is as a potent trap for singlet
oxygen, but much less effective in terminating free radical chain reactions and the vitamin E
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18 Coronary Artery Diseases
is an excellent terminating free radical chain reaction. The protect effect against LDL
oxidation is more effective with use of vitamin E than C. This difference may be because
vitamin C is distributed exclusively in the aqueous phase, whereas vitamin E takes up
residence predominantly in lipoprotein (Witztum and Steinberg, 2001).
HDL normally plays an anti-atherogenic role, unlike LDL. The protective capacity of HDL
has been ascribed primarily to its ability to remove excess cholesterol from peripheral
tissues in the reverse cholesterol transport pathway. However, recent studies have
suggested more mechanisms. For example, HDL can inhibit LDL oxidation and this may
contribute to inverse association between plasma HDL levels and risk of developing
atherosclerosis. These protective effects of HDL have been attributed to the various proteins
associated with HDL. Paraoxonase-1 is an enzyme associated with HDL in blood and has
been reported to posse antioxidant and anti-inflammatory properties. This enzyme is able to
hydrolyze oxidized phospholipids and to destroy the biologically active lipids in ox-LDL.
There is growing evidence that reduced activity of HDL-associated paraoxonase-1 is
predictive of vascular disease (Jayakumari & Thejaseebai, 2009).
4. Hypertension
Previous studies have indicated that hypertension and hypercholesterolemia frequently co-
exist, causing what is known as “dyslipidemic hypertension”. The combination of these
factors more than additively increases the risk of cardiovascular disease events compared
with the occurrence of one alone (Wong et al., 2006). The resultant oxidative stress is
considered a unifying mechanism for hypertension and atherosclerosis.
Hypertension development is intrinsically linked with vascular function and structural
changes, including endothelial dysfunction, altered contractility and vascular remodelling.
One of the key characteristics of hypertension is increased peripheral resistance, due largely
to a reduced lumen diameter of the resistance vessel, and a small change in diameter can
significantly impact on vascular resistance. The small arteries and arterioles that determine
peripheral resistance undergo both structural and functional changes in hypertension.
Examples of these changes include endothelial function, vascular smooth muscle growth,
extracellular matrix deposition and vascular inflammation, altering contractility and
vascular remodelling (Paravicini & Touyz, 2006).
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Coronary Artery Disease and Oxidative Stress 19
xanthine oxidase catalyses the oxidation of hypoxanthine and xanthine to form O2•-, and is
known to be present in vascular endothelium. Although xanthine oxidase-derived O2•- has
been primarily studied in the context of ischemia-reperfusion injury and heart failure, there
is also some evidence to suggest involvement in the endothelial dysfunction seen in
hypertension. Nitric oxide synthase (NOS) can also contribute to ROS production, as all
three NOS isoforms have been shown to be susceptible to the uncoupling that leads to the
formation of O2•- (rather than NO•) under certain conditions. Many studies have shown that
the major source of ROS in the vascular wall is nonphagocytic NAD(P)H oxidase, which
utilizes NADH/NADPH as the electron donor to reduce molecular oxygen and produce
O2•-. Activation of this enzyme is regulated by many vasoactive hormones, growth factors
and mechanical stimuli (shear stress and stretch) (Higashi et al., 2009).
The biomechanical forces influence the redox signalling. Two main forces acting on the
blood vessel wall are shear stress (movement of blood) and stretch (luminal pressure). Shear
stress and cyclic mechanical stretch influence vascular function and structure, in part, by
stimulating production of NO• and ROS. Summarizing, the biomechanical forces increase
activation and expression of endothelial NOS and stimulate production of O2•- and H2O2
(Paravicini & Touyz, 2006). Again, remembering that O2•- and NO• can form ONOO-;
increased vascular pressure in hypertension is associated with stretch of endothelial and
vascular smooth muscle cells, which can directly activate NAD(P)H oxidase to generate
ROS. This effect may be amplified by activation of the rennin-angiotensin system. Increased
oxidative stress in response to stretch contributes to activation of pro-inflammatory
transcription factors, activation of growth-promoting MAP kinases, upregulation of
profibrogenic mediators and altered vascular tone, important processes contributing to the
vascular phenotype associated with hypertension (Paravicini & Touyz, 2006).
As discussed before, the excessive ROS have a central common pathway by which disparate
influences may induce and exacerbate hypertension. Furthermore, a significant number of
epidemiological and clinical trial data suggest that diets known to contain significant
concentrations of naturally occurring antioxidants appear to reduce blood pressure and may
reduce cardiovascular risk. Because of this, there is much interest in identifying key,
naturally occurring antioxidants to both prevent and treat hypertension (Madamanchi et al.,
2005). As in hypercholesterolemia, the focus is on vitamins E and C, and also vitamin A. The
interest in vitamin A derivates has turned to lycopene, a potent antioxidant found in
tomatoes. One small study has shown a reduction in blood pressure with tomato extract-
based intervention. Vitamin C antihypertensive efficacy has been evaluated in small studies,
showing modest reductions in blood pressure in both normotensive and hypertensive
populations. With regard to vitamin E, small studies show either no effect or a pressor effect
from supplementation. It is important to take care with the use of higher doses of
supplements, since there is the risk of an antioxidant becoming pro-oxidant when used at
high doses, for example, the ascorbate increase the risk of forming oxalate renal calculi
(Kizhakekuttu & Widlansky, 2010). The addition of vitamins, the L-arginine, flavonoids and
mitochondria-targeted agents are part of a target group of studies. L-arginine is an amino
acid and the main substrate for the production of NO• from NOS, and reduced levels lead to
uncoupling of NOS resulting in the generation O2•- (low levels could contribute to
hypertension). L-arginine supplementation could reduce blood pressure allowing for a
restoration of normal NO• bioavailability. There are studies demonstrating that flavonoids
can inhibit NADPH oxidase and increase NOS-specific NO• production, but investigation
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20 Coronary Artery Diseases
5. Conclusion
Throughout this chapter we have seen the numerous connections between heart disease,
associated diseases and oxidative. Therefore, we cannot talk of homeostasis or change it
without talking about redox balance. Any event that alters the delicate balance between
defences and ROS moves the scales and triggers oxidative stress. Luckily our bodies are
adapted to these constant changes, but only to a limited extent. Minor damage accumulates
over the years. The fittest survive and we must be aware that not escaping natural selection,
it continues to act upon us.
An alert on the evaluation of data involving oxidative stress: strict criteria are needed. For
example, studies of ascorbic acid supplementation in rats and mice should be evaluated
very carefully since these species synthesize vitamin C, while humans do not. Extrapolation
of this data type for the human species must be carefully evaluated if it is to have any value.
In the case of human data it must not be forgotten that the effect of an antioxidant that
shows promise for a patient group cannot be extrapolated to healthy humans for example.
In addition, dietary supplements that may be beneficial for the chronically ill should not be
recommended for healthy people. What may be an antioxidant to one group can be pro-
oxidant to another. A simple explanation of why: chemical reactions are reversible. The
direction of the reaction in one group may be different from the direction of the reaction in
the other group. The inclusion of a reactant or product may mean the reactions favouring or
inhibiting the reactions that follow.
As we have learned over the past years for various diseases that afflict humanity, coronary
heart disease can be triggered by many environmental and genetic factors. The disease in
itself can trigger numerous other changes altering the homeostasis of the organism. Where is
oxidative stress involved? Is it a cause or consequence? These questions are difficult to
answer as we cannot address this issue without being aware of the chemistry of reactive
species; we only know them with a solid knowledge of basic chemistry, which leads us to
basic biochemistry, a deep knowledge of cell biology, physiology and so on. Molecular
biology and genetics will help us with information no less important. Therefore, we need
many more research groups than in the past century and in the clinical area,
multidisciplinary cooperation. Maybe this is the biggest challenge for the 21st century.
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24 Coronary Artery Diseases
www.intechopen.com
Coronary Artery Diseases
Edited by Dr. Illya Chaikovsky
ISBN 978-953-51-0238-0
Hard cover, 332 pages
Publisher InTech
Published online 07, March, 2012
Published in print edition March, 2012
This book has "wide geography" both literally and figuratively. First of all, this book brings together
contributions from around the world, both from post-industrial countries and developing world. This is natural,
because coronary artery disease is becoming pandemic worldwide. CAD is the single most frequent cause of
death in developed countries, causes about 1 in every 5 deaths. Mortality from cardiovascular disease is
predicted to reach 23.4 million in 2030. Moreover, in the developing world, cardiovascular disease tends to
affect people at a younger age and thus could negatively affect the workforce and economic productivity. The
morbidity, mortality, and socioeconomic importance of CAD make its diagnosis and management fundamental
for all practicing physicians. On another hand, the book widely represents "geography" of CAD itself, i.e. many
various aspects of its pathophysiology, epidemiology, diagnosis, treatment are touched in this book. This book
does not pretend on complete and integral description of the Coronary artery disease. Rather, it contains
selected issues on this complex multifactorial disease. Nevertheless, we hope that readers will find Coronary
Artery Disease useful for clinical practice and further research.
How to reference
In order to correctly reference this scholarly work, feel free to copy and paste the following:
Mara S. Benfato, Tássia M. Medeiros and Tiago B. Salomon (2012). Coronary Artery Disease and Oxidative
Stress, Coronary Artery Diseases, Dr. Illya Chaikovsky (Ed.), ISBN: 978-953-51-0238-0, InTech, Available
from: http://www.intechopen.com/books/coronary-artery-diseases/coronary-artery-disease-and-oxidative-
stress-