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653
Editorial Comment
Is NO an
Endogenous Antiatherogenic Molecule
John P. Cooke, Philip S. Tsao
E
ndothelium-derived relaxing factor is now
known to be nitric oxide (NO) or NO bound to
a carrier molecule, possibly in the form of a
nitrosothiol or nitrosoheme.
13
NO is derived from the
metabolism of L-arginine by NO synthase, which is
expressed by a number of cell types, including endothe-
lial cells, neurons, macrophages, platelets, and vascular
smooth muscle cells.
4
See pp 746, 753
NO is a potent vasodilator that activates soluble
guanylate cyclase, thereby increasing intracellular levels
of cyclic GMP. In addition, NO exerts an inhibitory
influence on cell proliferation and adhesion. The pro-
liferation of vascular smooth muscle cells or lympho-
cytes in culture is inhibited by exogenous NO donors as
well as endogenous NO.
5
-
6
Platelet adhesion and aggre-
gation as well as monocyte adhesion and chemotaxis a re
negatively regulated by this molecule.
79
These in vitro
studies indicate that NO suppresses a number of key
processes that are involved in atherogenesis. It seems
logical, therefore, that a reduction in the activity of
vascular NO would promote atherogenesis. Indeed, one
of the earliest abnormalities to occur in hypercholester-
olemic animals and hum ans is a reduction in the activity
of vascular NO, as manifested by impaired endotheli-
um-dependent vasodilation. This occurs well before any
structural changes in the vessel wall.
This impairment in endothelium-depend ent vasodila-
tion is reversible in hypercholesterolemic animal models
and humans by intravenous infusion of the NO precur-
sor L-arginine.
1013
The effect of L-arginine to normalize
endothelium-dependent vasodilation is likely due to its
metabolism to NO, since the effect is not mimicked by
D-arginine (which is not a substrate for NO syn-
thase).
10
-
12
Chronic administration of supplemental di-
etary arginine to hypercholesterolemic rabbits is also
associated with an improvement in endothelium-depen-
dent vasodilation.
14
The sustained enhancement of vas-
cular NO activity is paralleled by a striking inhibition of
intimal lesion formation in these animals.
14
Dietary
arginine also exerts an inhibitory effect on neointimal
lesion formation after balloon injury in this animal
From the Section of Vascular Medicine, Division of Cardiovas-
cular Medicine, Stanford U niversity School of M edicine, Stanford,
alif
Correspondence to John P. Cooke, MD, PhD, CVRC, Division
of Cardiovascular Medicine, Stanford University School of Medi-
cine, Stanford, CA 94305.
model.
15
Therefore, the weight of the available evidence
suggests that vascular NO exerts an inhibitory effect on
key processes in atherogenesis.
In this issue of
Arteriosclerosis and Thrombosis,
Naruse and colleagues
16
add support to this hypothesis
by demonstrating that chronic inhibition of NO synthase
accelerates atherogenesis. New Zealand White rabbits
were fed standard chow or a 2 cholesterol diet; some
animals in each group also received in their drinking
water a low (80 mg/mL) or high (160 mg/mL) dose of
nitro-L-arginine methylester
( L - N A M E ) ,
an inhibitor of
NO synthase. After 8 or 12 weeks, the animals were
killed to allow studies of vascular reactivity and histo-
morphometry. As expected, the hypercholesterolemic
animals had impaired endothelium-dependent relax-
ation. Administration of L - N A M E caused a further
impairment of endothelium-dependent relaxation in
hypercholesterolemic animals. Parallel changes were
observed in vascular structure, with the thoracic aortas
from the L-NAME-treated hypercholesterolemic ani-
mals manifesting greater lesion surface area. The data
suggest that impairment of NO synthesis promotes
a therogenes is . However , ora l adminis tra t ion of
L - N A M E augmented serum cholesterol values in the
hypercholesterolemic animals, and it is possible that this
played some role in the acceleration of lesion
development.
This confounding variable was obviated in the inves-
tigation by Cayatte and colleagues.
17
These investigators
administered a similar dose of L - N A M E by osmotic
minipump; subcutaneous delivery of
L - N A M E
was not
associated with any change in lipid profile or hemody-
namics. It is possible that the effect of the NO synthase
antagonist to alter the lipid profile is a unique effect of
oral administration and may indicate an interesting
interaction between the mesenteric NO synthase system
and lipid absorption or metabolism. Despite this and
other methodological differences between the two stud-
ies (composition of the cholesterol diet, length of treat-
ment, and type of morphometric analysis), the findings
are strikingly similar. In each case, chronic administra-
tion of NO synthase antagonists is associated with
inhibition of endothelium-dependent vasodilation and a
significant increase in the severity of intimal lesions.
The mechanisms of this intriguing effect remain un-
explained. Moreover, it is not clear whether the effect of
the NO synthase antagonist is due to inhibition of
endothelium-derived NO and/or NO elaborated from
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654 Arteriosclerosis and Thrombosis Vol 14, No 5 May 1994
other cell types (macrophages, platelets, or vascular
smooth muscle cells).
Recent studies from our laboratory support a role for
endothelium-derived NO .
18
New Zealand White rabbits
were fed normal chow or a 0.5 cholesterol diet; some
animals received supplemental dietary arginine,
whereas others received nitroarginine (the NO synthase
antagonist). After 2 weeks the animals were killed and
the thoracic aortas harvested for functional binding
studies and measurement of nitrogen oxide by chemilu-
minescence. We found that the elaboration of vascular
NO was increased in hypercholesterolemic animals that
had received supplemental arginine; vascular NO re-
lease was inhibited in animals that had received ni-
troarginine. Binding of monocytoid cells to the vessel
wall ex vivo was increased in hypercholesterolemic
animals and was increased to a greater degree in
animals that had received nitroarginine. By contrast,
there was a reduction in cells bound to the thoracic
aortas from hypercholesterolemic animals that had re-
ceived dietary arginine. To conclude, changes in vascu-
lar NO elaboration were associated with reciprocal
alterations in endothelial adhesiveness.
Is this alteration of endothelial adhesiveness due to
an inhibitory effect of N O on t he activation of adhesion
molecules and /or th e expression of chemotactic pro-
teins? Bath and colleagues
9
have found that exogenous
NO inhibits adherence of mononuclear cells to porcine
aortic endothelial cells in culture and inhibits in vitro
chemotaxis stimulated by Af-formyl-methionyl-leucyl
phenylalanine. More recently, Zeiher and colleagues
19
have reported that the NO d onor SIN-1 inhibits mRN A
expression and secretion of monocyte chemotactic pro-
tein-1 in primary cultures of human umbilical vein
endothelial cells. Thus, endogenous NO may modulate
endothelial-monocyte interactions. In addition, NO in-
terferes with the elaboration of superoxide anion and
may reduce the oxidative modification of low-density
lipoprotein by macrophages.
20
'
21
Although the available evidence suggests that vas-
cular NO inhibits de novo formation of intimal lesions,
the role of NO in the presence of preexisting lesions
remains to be determined. It is possible that in the
setting of established lesions, vascular NO could pro-
mote cell injury. Activated macrophages generate
superoxide anion and NO, which combine to form
peroxynitrite anion, a highly reactive free radical.
22
The cytotoxic effects of peroxynitrite anion are in part
mediated by membrane lipid peroxidation as well as
nitrosation of tyrosine moieties regulating enzyme
function and signal transduction.
23
Furthermore, in
large quantities, NO has cytotoxic effects mediated by
nitrosylation, mono- and poly-ADP ribosylation, and
interactions with metal-containing proteins that lead
to the inhibition of enzymes required for cellular
metabolism and DNA synthesis.
2427
However, even
these effects of NO could serve to suppress cellular
proliferation, inflammation, and lesion growth.
62 8
To
conclude, future investigations will be devised to elu-
cidate the mechanisms and conditions under which
endogenous NO inhibits atherogenesis. Knowledge of
these mechanisms may lead to new therapeutic strat-
egies for atherosclerosis and restenosis.
Acknowledgments
This work was supported in part by grants from the National
Heart, Lung, and Blood Institute (1PO1HL418638); the Uni-
versity of California Tobacco Related Disease Program
(IRT215); the Institute of Biological and Clinical Investigation
of Stanford University; and the Peninsula Community Foun-
dation. Dr Tsao is the recipient of a National Service Research
Award (1F328HL08779). Dr Cooke is the recipient of the
Vascular Academic Award from the National Heart, Lung,
and Blood Institute (1KO7HCO2660).
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Cooke
and Tsao Editorial Comment 655
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J P Cooke and P S TsaoIs NO an endogenous antiatherogenic molecule?
Print ISSN: 1079-5642. Online ISSN: 1524-4636Copyright 1994 American Heart Association, Inc. All rights reserved.
Avenue, Dallas, TX 75231is published by the American Heart Association, 7272 GreenvilleArteriosclerosis, Thrombosis, and Vascular Biology
doi: 10.1161/01.ATV.14.5.6531994;14:653-655Arterioscler Thromb Vasc Biol.
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