162
TCM Vol. 9, No. 3/4, 2001
Emma Meagher and Daniel J. Rader are from
the Department of Medicine and Center for
Experimental Therapeutics, University of
Pennsylvania Health System, Philadelphia,
Pennsylvania.
* Address correspondence to: Emma
Meagher, MD, University of Pennsylvania
Medical Center, Hospital of the University of
Pennsylvania, 9053 West Gates Pavilion, 3400
Spruce Street, Philadelphia, PA 19104, USA.
Tel.: 215-662-2174; fax: 215-614-0378; e-mail:
emma@spirit.gcrc.upenn.edu.
© 2001, Elsevier Science Inc. All rights
reserved. 1050-1738/01/$-see front matter
Oxidation is believed to play a role in
the pathogenesis of atherosclerosis. Oxi-
dation of low-density lipoprotein (LDL)
may be one mechanism by which LDL is
modified, leading to uptake by macro-
phages and formation of the foam cell
(Witztum and Steinberg 1991). Oxida-
tion of LDL may also create oxidized lip-
ids that exert a pro-inflammatory effect
(Witztum and Berliner 1998). Further-
more, oxidation of other lipids and pro-
teins within the vessel wall could promote
inflammation and atherosclerosis (Ber-
liner et al. 1995). Abundant data from
epidemiologic observational studies sug-
gest that greater intake of antioxidant vi-
tamins such as vitamin E, vitamin C,
and beta carotene are associated with
reduced risk of atherosclerotic vascular
disease (Rimm and Stampfer 2000).
These combined observations have led
to the concept that supplementation
with antioxidant vitamins could be used
therapeutically to reduce risk of cardio-
vascular disease. In this article, we re-
view two categories of evidence that ad-
dress this issue: (1) animal studies with
antioxidants, where the readout is quan-
titation of atherosclerosis; and (2) hu-
man clinical trials with antioxidants,
where the primary or secondary end-
point is clinical cardiovascular events.
• Animal Studies
Animal models of atherosclerosis have
been used to test the hypothesis that ad-
ministration of antioxidants would re-
duce the progression of atherosclerosis
and have provided substantial insights.
Crawford et al. (1998) used combined
dietary antioxidants (0.1% vitamin E,
0.5% beta carotene, and 0.05% vitamin
C) in LDL receptor-deficient mice fed a
high-fat, high-cholesterol diet. LDL oxi-
dation was markedly inhibited in the an-
tioxidant group. The cross-sectional sur-
face area of fatty streak lesions in the
aortic sinus was reduced by 60% in
the antioxidant group compared with
controls. Pratico et al. (1998) used vita-
min E alone in apolipoprotein E- (apoE)
deficient mice fed a chow diet. Supple-
mentation with vitamin E significantly
reduced the generation of isoprostanes,
a marker of in vivo oxidative stress, and
aortic lesion areas were reduced signifi-
cantly by vitamin E. A recent report of
a new mouse model confirms the im-
portance of vitamin E in preventing
atherosclerosis in mice. Vitamin E defi-
ciency caused by disruption of the alpha-
tocopherol transfer protein gene was
associated with increased levels of iso-
prostanes in aortic tissue and increased
severity of atherosclerotic lesions in the
proximal aortas of apoE-deficient mice
(Terasawa et al. 2000). This mouse model
of vitamin E deficiency demonstrates
unequivocally that vitamin E deficiency
promotes atherosclerosis and supports
the hypothesis that lipid peroxidation
contributes to lesion development.
Shaish et al. (1995) found that dietary
supplementation with all-trans beta car-
otene in New Zealand White rabbits fed
a high-cholesterol diet significantly in-
hibited atherosclerotic lesion formation.
Tangirala et al. (1995) used the antioxi-
dant N,N
Ј
-diphenyl 1,4-phenylenediamine
(DPPD) in apoE-deficient mice fed a
high-fat high-cholesterol diet. Lipopro-
teins from DPPD-treated animals were
more resistant to copper-induced oxida-
tion than lipoproteins from control ani-
mals. Atherosclerosis was significantly
reduced by 36% in the DPPD-treated
mice. Cynshi et al. (1998) used the anti-
oxidant BO-653 (2,3-dihydro-5-hydroxy-
2, 2-dipentyl-4,6- di-tert-butylbenzofuran)
in rabbit and mouse models of athero-
sclerosis and demonstrated significant
reductions in atherosclerosis in all models
Antioxidant Therapy and
Atherosclerosis: Animal and
Human Studies
Emma Meagher* and Daniel J. Rader
Oxidation of LDL cholesterol appears to play a central role in the
pathogenesis of atherosclerosis. Animal models of atherosclerosis have
elucidated this process and have demonstrated an antioxidant effect of
vitamin administration that has been correlated with delayed progres-
sion or regression of atherosclerosis. However, clinical trials of antiox-
idants present a confused picture. Explanations proposed for the dis-
crepancy in results include differences in patient characteristics, the
antioxidant content of their diets and dose selection. However, a strik-
ing feature of these trials is the absence of a biochemical basis for
patient inclusion or dose selection. Reliable, quantitative indices of free
radical induced modification of lipids , such as F2 - isoprostanes have
emerged. Future trials of anti-oxidant therapy in cardiovascular dis-
ease should be targeted toward patients with high levels of oxidant
stress or patients with depletion of endogenous antioxidants. The dose
of anti-oxidant should be chosen based on a surrogate readout, such as
F2 isoprostanes, that is a reliable, reproducible and easily obtainable in
vivo measure of oxidant stress.
(Trends Cardiovasc Med 2001;11:162–
165).
© 2001, Elsevier Science Inc.