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Antioxidants and cardiovascular disease

Authors:
Francesco Violi at Sapienza University of Rome
Francesco Violi
Roberto Cangemi at Sapienza University of Rome
Roberto Cangemi
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Oxidative stress appears to play a key role in the pathogenesis of atherosclerosis. Agents that prevent the oxidation of low-density lipoprotein have reduced the development and progression of this disease in a range of in vitro experiments and animal models. In the last decade, many trials of antioxidants in patients with cardiovascular disease have been conducted, but the results have been ambiguous. The reason for the disappointing findings is unclear, but one possible explanation is the lack of identification criteria for patients who are potential candidates for antioxidant treatment. This review analyzes data reported to date, in order to determine whether these clearly support the premise that patients at risk of cardiovascular disease may be candidates for this therapeutic option.
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Antioxidants and cardiovascular disease
Francesco Violi*
&
Roberto Cangemi
Address
IV Divisione di Clinica Medica
Viale del Policlinico 155
Roma 00161
Italy
Email:
francesco.violi@uniromal
.it
*To whom correspondence should be addressed
Current Opinion in Investigational Drugs
2005
6(9):895-900
O
The Thomson Corporation
ISSN 1472-4472
Oxidative stress appears to play a key role in the pathogenesis of
atherosclerosis. Agents that prevent the oxidation of low-density
lipoprotein have reduced the development and progression of this
disease in a range of in vitro experiments and animal models. In
the last decade, many trials of antioxidants in patients with
cardiovascular disease have been conducted, but the results have
been ambiguous. The
reqson
,
for the disappointing findings
is
unclear, but one possible explanation is the lack of identification
criteria for patients who are potential candidates for antioxidant
treatment. This review analyzes
data reported to date, in order to
determine whether these dearly support the premise that patients
at risk of cardiovascular disease
may
be
candidates for this
therapeutic option.
Keywords
Antioxidant, atherosclerosis, cardiovascular
disease, oxidative stress, vitamin
C,
vitamin E
Introduction
Oxidative stress' is believed to play a crucial role in the
initiation and progression of atherosclerosis. Oxidation of
low-density lipoprotein (LDL) within the vessel wall
represents a key step in the accumulation of LDL by
resistant macrophages, which ultimately become the foam
cells of atherosclerotic plaque. Enzymatic and
non-
enzymatic oxidation of LDL seems to be involved in this
process, but its relevance in the evolution of human
atherosclerosis is still unclear
[I*].
One important
consideration is the discrepancy between preclinical studies
and clinical trials with antioxidants. which have provided
divergent results. Most trials of antioxidants in experimental
models of atherosclerosis have demonstrated that this
treatment can retard the progression of the disease, but the
results of clinical trials are conflicting
[I*],
in that both
positive and negative effects have been reported.
Investigations of antioxidants for use in the prevention of
atherosclerosis have stemmed from observational trials that
demonstrated the existence of an inverse relationship
between the consumption of antioxidant vitamins and the
risk of cardiovascular events. On the basis of these data.
almost all of the trials have been conducted on the
assumption that supplementation with vitamins
C
and E
would represent a useful approach for preventing
cardiovascular disease. However. candidates for antioxidant
treatment were not accurately defined: any patients at risk of
cardiovascular events have been indiscriminately enrolled in
these trials. In contrast, we argue that since antioxidant
status represents an important marker of oxidative stress
121.
the determination of this status may be useful for more
accurate identification of suitable candidates for antioxidant
treatment. In order to substantiate this hypothesis. data
inherent to oxidative stress and antioxidant status in patients at
risk of cardiovascular disease. and in patients included in
observational and interventional trials, have been reviewed. As
antioxidant vitamins, vitamins
E
and
C
have been the focus of
the most important research in this field, thus our analysis
concentrates essentially on the clinical relevance of these
vitamins in patients with cardiovascular disease.
Cardiovascular disease risk factors and
oxidative stress
Endothelial dysfunction and intimal-medial thickness are
considered the early steps in the development of
atherosclerosis. Each characteristic lesion of this disease
represents a different stage in a chronic inflammatory
process in the artery: in fact, the lesions of atherosclerosis
represent a series of highly specific cellular and molecular.
responses that can be described as an inflammatory disease
131.
Possible causes of endothelial dysfunction that lead to
atherosclerosis include hypercholesterolemia. hypertension,
diabetes mellitus, cigarette smoking, elevated plasma
homocysteine concentrations, infectious micro-organisms
and ageing. It has been shown how each of these factors.
alone and in combination, is associated with atherosclerotic
disease
141.
This review will focus on the association of all of
these factors with oxidative stress.
Free radical formation can mediate some of the effects of
hypertension. Several studies strongly suggest that
enhanced oxidative stress may represent an important
trigger for atherogenesis elicited by angiotensin
I1 (Ang 11).
Ang I1 is a potent vasoconstrictor and is often elevated in
patients with hypertension. It also increases smooth-muscle
hypertrophy and lipoxygenase activity, which. in turn, can
increase inflammation and the oxidation of LDL.
Griendling et a1
[5]
examined the effect of Ang I1 on superoxide
anion
(0;) production by smooth-muscle cells, and
demonstrated that exposure of these cells to Ang
I1 elicited
enhanced production of
O;.This effect was mediated by NADH
and NADPH oxidase activation, likely via intracellular
mobilization of fatty acids, such as
arachidonic acid. These data
have important pathophysiological implications, due to the
effect of
0;
on vascular motility. Oxidative stress may have a
role in hypertensive patients, in whom a reduced vasodilating
response to acetylcholine has been demonstrated. In such
patients, the administration of vitamin
C
has restored
acetylcholine-induced vasorelaxation, suggesting a role for
oxygen free radicals in inducing vascular dysfunction in
individuals with hypertension
[6*].
Blood analysis of lipid peroxides or measurement of urinary
excretion of isoprostanes provided evidence that oxidative
stress is enhanced in patients with diabetes
171.
The impact
of these data in the context of atherosclerosis progression is
still unclear, but there is some evidence supporting a role for
oxidative stress as a contributor to the deterioration of
vascular disease. For example, an important finding was that
endothelium-dependent vasodilatation was reduced in patients
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