Diseases Caused by Age-Related Oxidative Stress

Review Article
The Protective Effect of Lipoic Acid on Selected Cardiovascular
Diseases Caused by Age-Related Oxidative Stress

Beata Skibska1 and Anna Goraca2
Department of Applied Pharmacy, Department of Pharmacy, Medical University of Lodz, Muszynskiego 1, 90-151 Lodz, Poland
Department of Cardiovascular Physiology, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland
Correspondence should be addressed to Beata Skibska; beata.skibska@umed.lodz.pl
Received 11 December 2014; Revised 16 March 2015; Accepted 25 March 2015
Academic Editor: Ersin Fadillioglu
Copyright © 2015 B. Skibska and A. Goraca. 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
Oxidative stress is considered to be the primary cause of many cardiovascular diseases, including endothelial dysfunction in
atherosclerosis and ischemic heart disease, hypertension, and heart failure. Oxidative stress increases during the aging process,
resulting in either increased reactive oxygen species (ROS) production or decreased antioxidant defense. The increase in the
incidence of cardiovascular disease is directly related to age. Aging is also associated with oxidative stress, which in turn leads
to accelerated cellular senescence and organ dysfunction. Antioxidants may help lower the incidence of some pathologies of
cardiovascular diseases and have antiaging properties. Lipoic acid (LA) is a natural antioxidant which is believed to have a beneficial
effect on oxidative stress parameters in relation to diseases of the cardiovascular system.

1. Introduction
Oxidative stress plays a key role in the development
of many cardiovascular diseases, including atherosclerosis,
hypertension, ischemia-reperfusion injury, and heart failure
(Figure 1). There are many factors associated with oxidative
stress, which lead to the development of these diseases. One
of the main factors is overproduction of ROS, together with
decreased nitric oxide bioavailability and reduced antioxidant
capacity in the vasculature [1].
Death due to cardiovascular diseases is the cause of
mortality in 80% of people aged over 65 years. In addition, the
aging process is associated with oxidative stress in the blood
vessels and in the heart, which leads to the development of
cardiovascular disease (CVD) [2].
According to the free radical theory of aging developed
by Harman, the antioxidant defense mechanisms become less
effective in people after the age of 40 [3, 4]. This results in
fatty acid oxidation and lipid peroxidation, with consequent
changes in the physical properties of cell membranes and
phospholipids. As they have long half-lives and increased
polarity, phospholipid peroxides are active intermediaries of

the oxidation and reduction chain [5], which may migrate
from point of origin to other places in the organism.
Excessive ROS production and weakened antioxidant
mechanisms lead to the occurrence of oxidative stress and
induction of apoptosis. ROS reacts with DNA, proteins, and
lipids, resulting in the accumulation of products, the onset of
degenerative processes, and, ultimately, the development of
many serious diseases and aging. Although aging is a natural
process, it is accelerated by ROS production.
Oxidative stress is an imbalance between production of
ROS present in cells and the biological ability to detoxify
the reactive intermediates or repair the harm caused [6].
Currently, antioxidants are used in order to reduce the
production of ROS in cells and limit their harmful effects on
the organism. One effective antioxidant is lipoic acid (LA).

LA is a natural antioxidant synthesized in the mito-
chondria of the liver and other tissues [7], which plays a

crucial role in metabolism. Its antioxidant properties were
first discovered in the 1950s [6] and later confirmed by
subsequent studies [8–11]. Its strong reduction and low
oxidation-reduction potential (−0.29 V) have made it the
subject of many studies from various fields of medicine.

Hindawi Publishing Corporation
Oxidative Medicine and Cellular Longevity
Volume 2015, Article ID 313021, 11 pages

2 Oxidative Medicine and Cellular Longevity


Heart failure



oxidative stress

Figure 1: The adverse effect of age-related oxidative stress on some cardiovascular diseases: atherosclerosis, hypertension, ischemia-
reperfusion, and heart failure.

It is currently regarded as one of the most potent cellular
oxidation regulators [12]. LA is a remarkable compound that
appears to slow the process of aging in animal experiments.
Considering the strong antioxidant properties of lipoic acid,
the purpose of this review is to present the protective role of
LA on selected cardiovascular diseases.
2. Age-Related Oxidative Stress in
Cardiovascular Diseases

2.1. Endothelial Dysfunction and Atherosclerosis. Endothe-
lium of the blood vessels is involved in many physiological

and pathological processes. It plays a very important role in
the physiological regulation of vascular tone, vascular smooth
muscle cell migration, cellular adhesion, and resistance to
thrombosis [13].
Pathological processes which occur in blood vessels
cause the endothelial balance to become dysregulated. This
endothelial dysfunction contributes to the development of
atherosclerosis, improper blood circulation, inflammation,
and even cancer progression [14]. Vascular dysfunction
is caused by reduction of nitric oxide levels, production
of vasoconstrictor/vasodilator factor imbalances, impaired
angiogenesis, endothelial cell senescence, and oxidative stress
[15]. Although there are several conditions that contribute to
endothelial dysfunction, increased oxidative stress seems to
play an important role.
The overproduction of ROS is a result of the adverse
effect of oxidative stress on cellular levels of nitric oxide
(NO), an important endothelial factor. Recent studies suggest
that NO is an important factor for the proper functioning
of endothelial cells, because it controls the function of
smooth muscle and exerts an antihypertensive effect at the
cardiovascular level [16].
NO is synthesized from l-arginine by the enzyme NO
synthase (NOS). There are three NOS isoforms: the neuronal

isoforms (nNOS), the constitutive endothelial isoform

(eNOS), and the inducible isoform (iNOS) [17]. The reduc-
tion of NO availability disturbs its vascular homeostasis.

Aging is a physiological process, but it also influences the
destabilization of endothelial cells.
This process, and its associated increased oxidative stress,
is one of the factors which may cause endothelial dysfunction.
The consequence of increased oxidative stress in aging is
inactivation of NO by high concentrations of O2
∙− produced
by the reaction of NO with ROS [18,19].The reaction between
NO and O2
∙− forms the peroxynitrite anion (ONOO−). This
form is known as a reactive nitrogen species (RNS) and
characterized high reactivity with proteins, DNA, and lipids.
Unlike O2
∙−, ONOO− can penetrate into the cardiovascular
cells and cause oxidative modifications within them [20].
Peroxynitrite has also been shown to induce microvascular

hyperpermeability by disrupting the adherens junction pro-
teins [21].

One in vitro study shows decreased eNOS expression in
aged human umbilical vein endothelial cells. This process
is associated with dysfunction of cell-cell junctions and
microvascular hyperpermeability [22]. It leads to severe
oxidative injury, which results in cell necrosis or apoptosis.
This has been confirmed by many other studies which suggest
that the decreased endothelial NO production promotes

endothelial cell apoptosis and leads to microvascular rarefac-
tion [23, 24].

Oxidative stress is known to activate redox-sensitive cel-
lular signaling pathways, which have in turn been implicated

in inflammation associated with vasculature subjected to
aging [25]. According to in vitro studies on endothelial
cells, this inflammation induces overproduction of ROS and
endothelial dysfunction in older rats [26].
In recent years, longevity genes have been identified that
affect lifespan and the rate at which the organism ages. For
example, defects in mouse Klotho gene have been shown to

Oxidative Medicine and Cellular Longevity 3
be associated with endothelial dysfunction, leading to the
premature development of atherosclerosis and, at the same
time, accelerated aging [27].
Mouse models of mild dyslipidemia have been found
to demonstrate endothelial dysfunction, for example, those

which are deficient in apolipoprotein E. This endothelial dys-
function is associated with stretch-induced hypercontractil-
ity and diminished endothelium-dependent vasorelaxation,

accompanied by decreased levels of NO and eNOS, as well as
increased plasma levels of IL-6, a proinflammatory cytokine

that reduces eNOS levels and activity. Endothelial dysfunc-
tion was found to precede the appearance of atherosclerosis

in a murine model of dyslipidemia [28].

Atherosclerosis is a pathological state of the vascula-
ture which progresses together with endothelial dysfunc-
tion caused by dyslipidemia, leading to the deposition of

inflammatory cells and lipids in the vascular wall. Therefore,
the state of the aging blood vessels, which are progressively

damaged, primarily impacts the development of atheroscle-
rosis. The oxidative stress theory of atherosclerosis indicates

that the production of ROS stimulates oxidized low-density
lipoprotein formation (ox-LDL) [29].

ox-LDL has many important properties which may pro-
mote atherosclerosis. It stimulates vascular ROS formation

and causes endothelial dysfunction via NOX activation and

endothelial (NO)-synthase (NOS) uncoupling [30]. In addi-
tion, Meisinger et al. note that it acts as a proatherogenic

marker [31] and that elevated levels of ox-LDL may predict
coronary heart disease events in healthy subjects. Moreover,
ox-LDL is known to promote oxygen radical generation in
human aortic endothelial cells (HEAC) by phosphorylating
the p66Shc adaptor protein at Ser36 [14]. Hence, oxidation of
LDL appears to contribute to the prooxidant environment in
atherosclerotic lesions.
Current research shows that endothelial dysfunction also
plays an important role in early and late mechanisms of
atherosclerosis development.
Atherosclerosis is known to result in vascular events such
as hypertension, ischemic heart failure, and heart failure.
2.2. Hypertension. Oxidative stress and aging are involved
in hypertension. Both lead to overproduction of reactive
oxygen species. The ROS generated in cardiovascular cells
cause various forms of pathological vascular damage in
blood vessels related to the promotion of cell growth, the
accumulation of extracellular matrix protein, inflammation,
and endothelial dysfunction, all of which are characteristic
features of the hypertensive vascular phenotype [32].
As in atherosclerosis, one of the major mechanisms by

which oxidative stress may promote hypertension is endothe-
lial dysfunction. Aside from impaired vascular expansion,

the most important effects of endothelial dysfunction are
those concerned with two substances produced by the
endothelium: NO and endothelin-1 (ET-1) [33]. An imbalance

between these substances interferes with vascular homeosta-
sis, leading to vasoconstriction and elevated blood pres-
sure [34]. Disturbed homeostasis is characterized by an

increase in the vasoconstriction factor ET-1 and a reduction

of the bioavailability of NO [35]. Experimental evidence
indicates that NO is inactivated by ROS, particularly O2

and H2O2, leading to endothelial dysfunction and vasocon-
striction [36]. Other studies have shown that ROS can be also

generated in response to ET-1 [37].
ET-1 is a vasoconstrictor peptide, which raises blood
pressure and induces vascular and myocardial hypertrophy
[38]. ET-1 production is known to be influenced by a
number of factors. Oxidative stress may cause modulation
of ET-1 and in ET-1-induced activation of various signaling
pathways [39]. In addition, aging may increase the release
of ET-1 from endothelial cells in humans and animals [40,
41]. In turn, in vitro studies have shown that ET-1 itself
activates many factors, including NFκB and TNF-α, which
are involved in cell growth, inflammation, and proliferation
[42–44]. These processes can also affect the development of

Along with NO deficiency and increased ET-1 produc-
tion, a dysfunctional endothelium also acts as a source

of other mediators and factors such as prostaglandin H2,
tromboxane A2, ROS and angiotensin II (AT II) that damage
vascular cells [45]. Both angiotensin II and endothelin-1
play important roles in age-related endothelial dysfunction
[46]. Angiotensin II stimulates ET-1 release and raises blood
pressure by a variety of actions [47] and is a potent activator
of nicotinamide adenine dinucleotide phosphate (NAD(P)H)
oxidase in vascular cells [48]. NAD(P)H is a major source of
ROS in the blood vessels and is considered to be a critical
determinant of the redox state of blood vessels [49]. Some
studies suggest that enhanced NAD(P)H-oxidase activity
can be observed in hypertension-induced oxidative stress
and subsequently endothelial dysfunction. Another study
confirms the role of NAD(P)H-oxidase on the formation of
ROS in blood vessels. The activation of NAD(P)H-oxidase
in cerebral blood vessels causes H2O2-mediated opening of
BKCa channels in cerebral arteries, leading to consequent

hyperpolarization and vasodilation [50]. In addition, oxida-
tive stress activates other enzymes, including mitochondrial

enzymes, NOS, and xanthine oxidase, which are produced
following ROS production and have a damaging influence on
blood vessels.

The relationship between oxidative stress and hyperten-
sion has been shown in many experimental models [51–54].

Similarly, the renin-angiotensin aldosterone system (RAAS)
is important in the pathogenesis of arterial ageing [55]. RAAS
is one of the most important hormonal systems; it oversees
the functions of the cardiovascular, renal, and adrenal glands
by regulating blood pressure, fluid volume, and sodium and
potassium balance. Disorders in RAAS function lead to
endothelium dysfunction, which may be caused, inter alia, by
age-related oxidative stress [56].

To summarize, hypertension may be triggered by a num-
ber of factors. However, oxidative stress and aging both exert

a significant influence.

2.3. Atherosclerosis-Ischemic Heart Disease. Age-related oxi-
dative stress also leads to cardiac ischemic and reperfusion

injuries. Aging and oxidative stress play important roles

4 Oxidative Medicine and Cellular Longevity
in the senescent heart. The aged myocardium has less
tolerance to ischemia and hemodynamic stress than the
young myocardium [57–59].
Many metabolic and biochemical changes in myocardial
tissue are the result of oxygen and nutrient deprivation during
ischemia. In most cases, the presence of atherosclerotic
plaques slowly leads to the narrowing of blood vessels and
impairs the blood supply to the heart. Long-term ischemic
heart disease can lead to myocardial infarction due to
myocardial hypoxia and accumulation of waste metabolites.
This can lead to damage to the cardiovascular and cell death
by apoptosis [60].
During reperfusion, the concentration of superoxide
anions (O2

∙−) and hydroxyl groups (OH−) from mitochon-
dria is greatly increased. Oxidative stress is then intensified

by the increased production of these ROS, which then results
in oxidation of mitochondrial proteins and mitochondrial
dysfunction [61].
ROS such as superoxide anions, hydrogen peroxide, and
hydroxyl groups can cause mitochondrial genomic damage

and a gradual decline in mitochondrial function in senes-
cent hearts [62]. Mitochondria from aged hearts have been

found to demonstrate reduced membrane potential, which
may contribute to lowered adenosine 5󸀠

-triphosphate (ATP)
synthesis [63]. This imbalance between the synthesis and
consumption of ATP significantly influences the metabolism
of the heart muscle, leading to greater oxygen consumption.

ATP deficiency is also associated with a rapid loss of myocar-
dial contractility, which can result in dysfunctions of the

cardiovascular system and arrhythmias [64].
ROS can also activate some biochemical pathways in
blood vessels, resulting in changes in cell function. In

response to angiotensin II induction, they can activate pro-
tein kinase B in vascular smooth muscle cells (VSMC), lead-
ing to VSMC hypertrophy [65].The activation of biochemical

signaling pathways promotes greater cellular dysfunction and
impairs cardiomyocyte functionality [66].
Increased levels of inflammatory markers such as TNF-
α, CRP, and IL-6 can be observed in ischemia-reperfusion
damage. These compounds and other cytokines can increase

the production of ROS in atherosclerosis by stimulating vas-
cular myocytes. Conversely, by inducing inflammation, ROS

may also further stimulate the production of inflammatory
Furthermore, other biomarkers of oxidative stress play

important roles in the pathophysiology of ischemia-reperfu-
sion damage in myocardial infarction. Extracellular biomark-
ers of ischemia-reperfusion damage include lipid peroxi-
dation products, plasma antioxidant vitamin levels, total

antioxidant capacity of plasma, and protein carbonylation.
In addition, such intracellular biomarkers as antioxidant
enzyme activity, thiol index (GSH/GSSG ratio), carbonyl
levels, and F2-isoprostane level can influence the degree of
oxidative stress [67].
In general, an imbalance between the demand for oxygen
and nutrients and the ability to deliver them to the heart
muscle, known as ischemia-reperfusion, is most commonly
caused by atherosclerosis, but oxidative stress and related
overproduction of ROS also play important roles. They cause

lipid, protein, and DNA oxidation, potentially contributing to
contractile failure [68].
Ischemia can lead to various diseases of the heart such as

heart failure and, ultimately, myocardial infarction, depend-
ing on the duration and extent of ischemia.

2.4. Heart Failure. The effects of oxidative stress on aging
on the vasculature and on the heart muscle are varied but
can lead to the development of heart failure (HF). Several
cardiovascular diseases are connected with HF, for example,
ischemic heart disease, atherosclerosis, hypertension, and
cardiac hypertrophy. Oxidative stress and ROS accumulation
contribute to all these and contribute to their progression.

In myocardial ischemia, hypoxia and reoxygenation ele-
vate ROS production in cardiac tissues, which leads to direct

oxidative damage to cellular components.
ROS influence the function of the extracellular matrix,
which is demonstrated by greater interstitial and perivascular
fibrosis [69].
On the cellular level, mitochondria are one of the major
sites for the generation of ROS, which is an undesirable side
product of the energy production. Therefore, mitochondrial
dysfunction increases the risk of heart failure. Among the
damage induced by ROS generated at the cellular level,
mitochondrial DNA (mtDNA) remains the major target [70].
In experimental models, it has been proven that mtDNA
deletions contribute to the phenotype of systolic heart failure
through increased mtROS [58].
Oxidative stress changes gene expression and influences
cell death in heart cells which are now known to exert an
influence on heart failure and myocardial remodeling. Heart

failure itself is known to involve a decrease in contractil-
ity, myocardial fibrosis, myocyte apoptosis, and metabolic

remodeling [71]. Metabolic remodeling in heart failure is
characterized by decreased cardiac energy production, which

is the result of a decrease in the level of ATP in cardiomy-
ocytes. This may lead to progressive impairments in substrate

utilization and mitochondrial biogenesis and function. In
addition to ATP deficiency, metabolic remodeling involves

changes in metabolic pathways that regulate essential, non-
ATP-generating cellular processes such as growth, redox

homeostasis, and autophagy [72]. A reduced supply of ATP
necessary for the contractile function of cardiomyocytes can
account for chronic heart failure.
One cause of these processes is increased oxidative stress,
which leads to the disruption of the structures of proteins,
lipids, and nucleic acids. Several studies have demonstrated
an association with these structural disorders and heart
failure [73, 74].
In the failing heart, overproduction of ROS leads to the
accumulation of superoxide anions, which may be generated
by both metabolic and enzymatic sources, including nitric
oxide synthase, NADPH oxidases, mitochondrial respiration,
and xanthine oxidase [75].
Xanthine oxidase (XO) in particular exerts an important
influence on heart failure. XO can also combine with other
compounds and enzymes and create reactive oxidants, as
well as oxide substrates. It has been found to be present in

Oxidative Medicine and Cellular Longevity 5
higher levels with greater activity in cases of heart failure.
This upregulation can contribute to the energy disorder in
myocardial cells [76].
Similarly, increased NAD(P)H activity has been observed
in myocardial cells from humans with heart failure [77, 78].
This increase is due partly to the presence of increased
concentrations of angiotensin II, which leads to an imbalance
in the oxidative/nitrosative system [27]. In addition, ROS
generated by NADPH oxidase proteins are also important in
redox signaling [79].
In summary, multiple factors are involved in the etiology
of heart failure, and oxidative stress is one of them. To
reduce or prevent the adverse effects of oxidative stress on
the organism, substances with antioxidant properties can be
applied. Research indicates that dietary supplementation by
exogenous antioxidants can play a key role in ameliorating
many of the effects of oxidative stress in cardiovascular
3. Protective Effect of Lipoic Acid (LA) on
Cardiovascular Diseases
Lipoic acid (LA) is a specific antioxidant; it can easily quench
radicals, has an amphiphilic character, and does not exhibit
any serious side effects [80]. LA a compound that contains
sulfur in the form of two thiol groups [81] acts as a cofactor for
several mitochondrial enzymes by catalyzing the α-ketoacid.
The antioxidant properties of LA are based on its ability to
directly scavenge ROS, its metal chelating activity, and its
potential to react with, and regenerate, other antioxidants
such as glutathione and vitamins E and C [82]. LA also
demonstrates anti-inflammatory properties.
An additional advantage of LA is its solubility both in
water and in fat, which allows it to travel to all parts of the
body [83]. Because of its special properties, it is able to enter
certain parts of the cell that most other antioxidants are not
able to reach.
This compound acts by many mechanisms and can
therefore be a very effective antioxidant. Hence, LA is used in
various diseases concerning age-dependent oxidative stress.
It can be particularly effective in cardiovascular diseases,
including ischemic heart disease, hypertension, heart failure,
and atherosclerosis, where it may slow aging and prolong
3.1. Effect of Lipoic Acid in Atherosclerosis. Many studies
have confirmed that LA can improve vascular function
and decrease the atherosclerotic plaque burden [84, 85]. By
chelating redox-active transition metal ions, LA is thought to
inhibit the Fenton-like-reaction mechanism and inhibit the
formation of OH−. As a consequence, lipid peroxidation is
inhibited in mitochondria [86].

A crucial regulator of vascular homeostasis is the renin-
angiotensin-aldosterone system (RAAS). A key role in the

pathogenesis of atherosclerosis is played by angiotensin II
(Ang II). It induces oxidative stress and creates superoxide
anions primarily through the activation of NAD(P)H-oxidase

in vascular cells and myocytes. In addition, Ang II acti-
vates intracellular signaling pathways and upregulates many

inflammation factors including chemokines, cytokines, and
growth factors, which have been implicated in atherosclerotic
plaque development.

LA reacts with ROS, such as superoxide anions, nor-
malizes NADPH oxidase activity, and can prevent Ang II-
induced macrophage, monocyte, and T cell infiltrations. It

is also thought that LA can block AT1 receptors, which
improves endothelial function and reduces plaque area in
atherosclerosis [87].
Many clinical studies have shown that the beneficial
effects of LA against Ang II are linked not only to scavenged

ROS, but also to NF-kappaB inhibition. LA reduces NF-κB-
mediated inflammatory responses by regulating the expres-
sion of proinflammatory genes and adhesion molecules

[88]. It also reduces the chemokine and adhesion molecules

involved in T cell trafficking to inhibition of monocyte-
endothelial interactions by atherosclerotic plaque.

Many animal and human studies report that LA supple-
mentation can result in reduced cholesterol levels [89, 90].

LA may also prevent LDL oxidation by reducing the concen-
trations of LDL-C, Ox-LDL, serum TC, and lipoprotein (a)

[Lp(a)], as well as other oxidative biomarkers [85].
Clinical studies confirm that LA may also reduce the

aortic expression of adhesion molecules and the accumula-
tion of aortic macrophages and proinflammatory cytokines,

resulting in reduced LDL level and triglyceride concentration
and elevated HDL [91, 92]. In animal models, 12-week
administration of LA reduced oxidative stress and improved
vascular reactivity in animals fed with a high cholesterol diet

[93]. LA may also be capable of initiating LDL receptor syn-
thesis in the liver, resulting in increased return of cholesterol

to the hepatic system and elevated synthesis of apoprotein A
component (a HDL particle moiety) for reversed cholesterol
transport [94–96].
Finally, it can be concluded that LA has a direct lipid
modulating action and an indirect effect on blood lipid levels,
leading to reduced risk of atherosclerosis. It is used as a
dietary supplement, either alone or with other oxidants; for
example, vitamins C and E may represent a helpful strategy
in reducing the adverse effects of oxidative stress.
3.2. Effect of Lipoic Acid in Hypertension. Hypertension

increases the production of various inflammatory biomark-
ers. These include chemokines, such as monocyte chemoat-
tractant protein 1 (MCP-1), adhesion molecules, such as

P-selectin, and cytokines, such as tumor necrosis factor-α
(TNF-α) and interleukin- (IL-) 6. This elevated production
of biomarkers results in reduced NO bioavailability, via
NO degradation in vessel cells, and excessive production of
endothelin I, which in turn impairs endothelium-dependent
vasodilation [97]. ROS, particularly O2

∙−, bind NO and form

highly reactive and dangerous ONOO−. This ONOO− pro-
duces a cascade of changes, which in turn lead to increased

tension within the blood vessels.
Lipoic acid may have a beneficial effect in preventing
the development of hypertension by lowering the level of

6 Oxidative Medicine and Cellular Longevity
inflammatory cytokines in the blood plasma, thus preventing
these pathological changes to vessel cells and normalizing
changes in blood pressure [98, 99]. Several clinical trials
have shown that LA inhibits the vascular overproduction of
endothelin I, the main vasoconstrictor [100]. Furthermore,
LA significantly increases the synthesis of NO, the main
vasodilator; it may also improve the redox state of the
plasma and improve endothelium-dependent NO-mediated
vasodilation. In addition, LA ameliorates the loss of eNOS
phosphorylation, which contributes to improved endothelial
function [101, 102]. It is also known to inhibit TNF-alpha
activation [103]. As LA is a good metal chelator, it may also
inhibit the production of adhesion molecules by monocytes,

thus improving endothelial function. In one study, LA sup-
plementation was found to reduce the aortic expression of

adhesion molecules and proinflammatory factors, such as
lowering the accumulation of aortic macrophages [96].
Furthermore, LA could potentially regulate intracellular
Ca2+ levels by preventing the modification of sulfhydryl
groups in the Ca2+ channels [104]. Another study shows that
LA increases tissue GSH levels, which otherwise decline with
age, by restoring glutathione peroxidase activity [105, 106].
The antioxidant properties of LA cause it to exert a
“rejuvenative” impact on mitochondria by protecting them
against the higher levels of ROS they produce during
the aging process. LA increases oxygen consumption and
mitochondrial membrane potential, while decreasing the
mitochondrial production of oxidants by amplifying the
activity of antioxidant mechanisms [107]. However, despite
LA supplementation not being particularly effective in this
regard, it can nevertheless significantly reduce blood pressure

when used in combination with other antioxidants such as L-
carnitine [108].

3.3. Effect of Lipoic Acid in Atherosclerosis-Ischemic Heart
Disease. Ischemia injury can follow oxidative stress and can
lead to significant morbidity and mortality. During ischemia,
specific changes in the antioxidant system can occur, resulting
in injury to organs such as the kidney, liver, or heart.
In ischemia, oxidative stress causes many complication

reactions involving adhesion molecules and cytokines, lead-
ing to massive release of ROS. This process increases the

production of tumor necrosis factor-alpha (TNF-α) and

interleukin-1 (IL-1) through activation of NF-κB. Further-
more, increases in intracellular Ca2+ concentration and MDA

levels result in decreases in GPx and SOD reactivity [109],
thus inducing contractile dysfunction, hypertrophy, fibrosis,
and cell death [110]. Contractile function and arrhythmias
may also be depressed [111]. Clinical studies indicate that up
to 50% of the final infarct may be attributable to ischemia
injury in both animals and humans [67].
LA counteracts the damage associated with the ischemia
experimental model. It can provide protection against

ischemia by inhibiting ROS production, blocking inflamma-
tion, and reducing myocardium apoptosis, as noted above.

Recent studies indicate that LA prevents postreperfusion

arrhythmias and protects cardiomyocytes from hypoxia-
induced death [112]. It induces cardioprotection through

a number of routes: inhibition of NOX4 activity leading to
NOS recoupling, improved NO bioavailability, and reduced
oxidative stress, leading ultimately to the preservation of

mitochondrial function. In addition, LA limits further dam-
age caused by ischemia by increasing Akt phosphorylation via

the activation of the PI3K/Akt pathway and the induction of
cytoprotective genes [113]. It also prevents decreases in ATP
content and the activation of proinflammatory factor NF-κB.
In animal models of ischemia, LA was found to ameliorate
cardiac dysfunction with reduced infarct size and lower levels
of myeloperoxidase, TNF-α, creatinine kinase, and lactate
dehydrogenase, while upregulating the expression of several
antioxidant enzyme genes [114]. Other studies report that
LA administration bestows significant protective effects by
raising MDA levels and lowering the activity of glutathione
peroxidase (GPx) and superoxide dismutase (SOD), the
enzymatic scavengers of ROS [109].
Another way to protect the cardiovascular system from

oxidative stress is based on its capacity to regenerate endoge-
nous antioxidants such as vitamins C and E. It also regener-
ates glutathione, which plays a very important role in main-
taining the balance between antioxidants and prooxidants.

LA may increase the levels of glutathione and other natural
antioxidants, thus preventing the progression of ischemia
3.4. Effect of Lipoic Acid in Heart Failure. Heart failure (HF)
may cause severe damage to the heart muscle via myocardial
fibrosis, ventricular remodeling, decreased contractility, and
increased myocyte apoptosis [14]. Mitochondrial damage
is central to the pathophysiology of HF. The mechanism
of mitochondrial dysfunction is connected with cellular
and mitochondrial damage which impairs the mechanical
properties of the heart. In age-related oxidative stress, a
reduced supply of energy from the mitochondria necessary
for the contractile function of cardiomyocytes is often noted

[116]. Therefore, one strategy in treating HF is the stimula-
tion of cardiac systolic function by targeting mitochondrial


Cardiomyocyte function is disturbed in HF, but not irre-
versibly [117]. The cardiomyocytes respond to oxidative stress

by increasing antioxidant system activity: increased thiore-
doxin system (Trx) activity has been observed, together with

greater mRNA expression of several antioxidant enzymes
[118]. Myocardial energy efficiency can be improved by up to
30% by using strategies based on increasing glucose oxidation
and decreasing fatty acid metabolism [117].
Many studies on animal models have confirmed that
LA can prevent progressive remodeling and even improve
cardiac function [119]. By acting as a cofactor for enzymatic

reactions within the mitochondria, it can improve mitochon-
drial function by conserving cellular energy [120]. Thus, LA

can influence mitochondrial antioxidant status, neutralize
ROS, and effectively attenuate mitochondrial damage caused
by oxidative stress and the aging process [121]. Antioxidants
such as LA are widely regarded as attractive novel agents
which can be employed to prevent oxidative stress when
targeted at the mitochondria [122]. Several studies have

Oxidative Medicine and Cellular Longevity 7
demonstrated that LA administration effectively attenuates
cardiac apoptosis [123, 124]. It has been found to attenuate
oxidative damage to the mitochondria, with increased GSH
levels and enhanced SOD activity being observed [123].
It has also been seen to mediate the elevation of cellular
defense, which may be associated with greater resistance
to ROS-elicited cardiac cell injury [124]. Finally, it has also
been demonstrated that LA reinforces cellular defenses by
inducing endogenous antioxidants and phase 2 enzymes
in cultured cardiac cells. These have been associated with
markedly increased resistance to ROS-elicited cardiomyocyte
injury [124].
All the above examples indicate that LA may be helpful
in treating HF caused by oxidative stress. It offers a number
of benefits concerned with preventing oxidative damage to
the mitochondria, on both molecular and genetic levels, even
when applied at low concentrations. Its use in this regard
merits further study.
4. Summary
In the last years, investigations in human and animal models

have provided abundant evidence that age-dependent oxida-
tive stress plays an important role in cardiovascular diseases.

Studies indicate that antioxidants prevent development of
many cardiovascular diseases and may even improve course

of diseases, such as atherosclerosis, hypertension, ischemia-
reperfusion, or heart failure. It is therefore disappointing that

very few applications have been found for antioxidants in
these diseases.
Lipoic acid can provide protection against ROS-induced
damage under conditions of elevated oxidative stress brought
on by the aging organism. It meets all the criteria for an ideal
antioxidant, because it may reduce adverse effects of oxidative
stress, has amphiphilic properties, and does not exhibit any
serious side effects [125].
However, the results of clinical trials intake of exogenous
antioxidant are contradictory. No beneficial effects were
reported in several studies in which only one synthetic
antioxidant was used. Therefore, a better antioxidant effect
can be achieved using more than one antioxidant.
ROS: Reactive oxygen species
LA: Lipoic acid
NO: Nitric oxide
RNS: Reactive nitrogen species
NOS: Nitric oxide synthase
CVD: Cardiovascular disease
ox-LDL: Oxidized low-density lipoprotein
TNF-α: Tumor necrosis factor-alpha
ET-1: Endothelin-1
AT II: Angiotensin II
NAD(P)H: Nicotinamide adenine dinucleotide phosphate
RAAS: Renin-angiotensin aldosterone system
ATP: Adenosine 5󸀠


HF: Heart failure
mtDNA: Mitochondrial DNA

GSH: Reduced glutathione
SOD: Superoxide dismutase.
Conflict of Interests
The authors declare that there is no conflict of interests
regarding the publication of this paper.
The study was supported by Grant no. 503/0-079-03/503-01
from the Medical University of Lodz.
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