Hypertension. 1995;25:155-161
(Hypertension. 1995;25:155-161.)
© 1995 American Heart Association, Inc.
Hypertension and the Pathogenesis of Atherosclerosis
Oxidative Stress and the Mediation of Arterial Inflammatory Response: A New Perspective
R. Wayne Alexander
From the Division of Cardiology, Emory University School of Medicine,
Atlanta, Ga.
Correspondence to R. Wayne Alexander, Division of Cardiology, Emory University School of Medicine, PO Drawer LL, Atlanta, GA 30322.
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Abstract
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Abstract Hypertension is a risk factor for the development of
atherosclerosis,
although the mechanisms have not been well elucidated.
As the
cellular and molecular mechanisms of the pathogenesis of
atherosclerosis
and the effects of hypertension are being more clearly
defined,
it becomes apparent that the two processes have certain common
mechanisms.
The endothelium is a likely central focus for the effect of
both
diseases. There is increasing evidence that atherosclerosis
should
be viewed fundamentally as an inflammatory disease. Atherogenic
stimuli
such as hyperlipidemia appear to activate the inflammatory
response by
causing expression of mononuclear leukocyte recruiting
mechanisms. The
gene for one of these, the vascular cell adhesion
molecule-1, is
controlled at least in part by transcriptional
factors regulated by
oxidative stress, which modifies the redox
state of the endothelial
cell. Alterations in the redox state
of the arterial wall also may
contribute to vascular smooth
muscle cell growth. In a somewhat
parallel fashion, there is
evidence that hypertension may also exert
oxidative stress on
the arterial wall. This article reviews evidence
that leads
to the postulate that hypertension predisposes to and
accelerates
atherosclerosis at least in part because of synergy between
elevated
blood pressure and other atherogenic stimuli to induce
oxidative
stress on the arterial wall.
Key Words: atherosclerosis hypertension, essential endothelium muscle, smooth, vascular stress
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Introduction
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Hypertension is not only a
well-established cardiovascular risk
factor but also increases the risk
of atherosclerosis. Clinical
trials have shown that, in the highest
quintile of diastolic
pressure, even with the added risks of high
cholesterol and
smoking, hypertension still contributes significantly
to risk
for atherosclerosis.
1 2 In laboratory studies in
which hypertension
was induced in the Watanabe heritable hyperlipidemic
rabbit,
Chobanian and his group
3 showed a synergistic
effect that caused
an intensification of atherosclerosis. In the total
surface
area of involvement of the abdominal aorta of these
endogenously
hypercholesterolemic animals, a dramatic enhancement of
lesion
formation accompanied the induced hypertension. The low-density
lipoprotein
(LDL) receptor in this rabbit strain has the same type of
molecular
defect as is found in familial hypercholesterolemia. Thus,
both
clinical and experimental data show that high (elevated) blood
pressure
enhances the development of atherosclerosis. In fact,
atherosclerosis
tends to occur only in those parts of the vascular
system subjected
to high pressure.
However, the mechanisms of this enhanced or synergistic effect are not
yet well defined. We still do not understand the fundamental nature of
atherosclerosis itself, although great progress has been made,
especially recently, in understanding and developing some unifying
hypotheses about the pathogenesis of the disease. This conceptual
process, in turn, has made it easier to begin to develop mechanistic
insights into the role of hypertension in exacerbating the
atherosclerotic process.
Atherosclerosis and hypertension are distinct disease entities;
everyone who has hypertension does not manifest extensive
atherosclerosis, nor is atherosclerosis always or even usually
accompanied by hypertension. The cardinal pathological features of
atherosclerotic lesion development are (1) the presence of
monocytes/macrophages and T cells, (2) their localization in large
conduit or elastic arteries in areas of low shear stress, (3)
proliferation and migration to the intima of medial smooth muscle
cells, (4) the deposition of increased amounts of connective tissue,
and (5) neovascularization.4 Hypertensive arteries are
thickened, and there may be increased smooth muscle cell mass and/or
cell number and increased deposition of connective
tissue.5 In considering the interactions of the two
diseases, it will probably be most useful to consider mechanisms or
consequences that are common to both. The purpose of this review is to
relate recently developed concepts of the pathogenesis of
atherosclerosis to shared mechanisms in hypertension, with a focus on
the molecular mechanism by which hypertension might facilitate the
development or progression of atherosclerosis. The subject has been
reviewed extensively in broader contexts.5 6 7 8
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The Importance of the Endothelium
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The logical initial focus in considering shared pathophysiological
mechanisms
is the endothelium, which has been intensely studied for the
last
15 to 20 years. Abnormalities of the endothelium underlie a
number
of human diseases and appear to be central to the pathogenesis
of
atherosclerosis. Changes in endothelial function and morphology
are
also cardinal features of hypertension.
9 New knowledge
about
common features of the endothelium in atherosclerosis and
hypertension
may contribute to understanding the effect of elevated
blood
pressure in the development of atherosclerosis.
The importance of the endothelium in the development of atherosclerosis
was first appreciated when it was observed that its removal facilitated
atherosclerotic lesion development in hypercholesterolemic animal
models.10 These observations led to the "response to
injury" hypothesis of atherosclerosis,10 in which it
was assumed that endothelial desquamation preceded lesion development.
It was shown subsequently, however, that the endothelium overlying
lesions is intact but morphologically altered (except over very
advanced, active lesions11 ). These findings led to the
concept of "dysfunction" of the endothelium.12 The
underlying assumption was that critical, initially unknown functions of
the normal endothelium that protect against atherosclerotic lesion
development go awry in the endothelial cells in lesion-prone areas.
The first direct evidence for endothelial dysfunction in human
atherosclerosis actually came from clinical investigations into the
disordered control of vasomotor tone in coronary artery
disease.13 The hypothesis tested was that, whatever the
nature of the putative endothelial dysfunction associated with the
development of atherosclerosis, the abnormalities would be general and
would extend to encompass the endothelium-dependent
control of vasomotor tone. The phenomenon of
endothelium-dependent vasodilation had been discovered
earlier.14 The endothelium was shown to release a
vasodilating humoral agent in response to various stimuli, including
acetylcholine and blood flow. This agent was called
endothelium-derived relaxing factor and subsequently
was shown to be nitric oxide.15 16 Nitric oxide diffuses
to the underlying vascular smooth muscle and causes relaxation by
stimulating guanylate cyclase to increase cyclic GMP.17 In
the cardiac catheterization laboratory, narrowed segments of coronary
arteries in patients with angiographic evidence of atherosclerosis
constricted in response to the endothelium-dependent
vasodilator acetylcholine, whereas normal smooth segments
dilated.13 Thus, the relation between atherosclerosis and
dysfunctional endothelium was established. As will be discussed
subsequently, the molecular mechanisms underlying the vasomotor
dysfunction may also contribute to the pathogenesis of atherosclerosis.
Certain of these molecular and metabolic abnormalities may also be
characteristic of the hypertensive arterial wall.
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Hyperlipidemia and Atherosclerosis
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The intimate relation between hyperlipidemia and abnormal
lipoprotein
metabolism and atherosclerosis has been appreciated for
many
years.
18 Indeed, the lipid-laden macrophage or foam
cell is
recognized as a hallmark of the disease. Despite the
recognition
of the association between hyperlipidemia and
atherosclerosis,
the precise molecular link has only recently begun to
be elucidated.
One of the seminal observations was that whereas native
LDL
was not taken up readily by macrophages, LDL that had been modified
by
exposure to endothelial cells was readily taken up and led to
the
formation of foam cells in vitro.
19 It was subsequently
established
that one of the important modifications of LDL that
permitted
its recognition by the scavenger LDL receptor on macrophages
was
oxidative modification of the lipoprotein.
20 Oxidized
LDL was
found to have protean biological effects on the vessel wall,
including
stimulation of cytokine production,
21 22
inhibition of endothelial
cell vasodilator function,
23 and
stimulation of growth factor
production.
24 In addition to
the importance of these observations
in providing mechanistic links
between lipoproteins and the
cell biology of atherosclerosis, they
raised the more general
possibility that abnormalities of the
oxidation-reduction state
in the vessel wall might be an important
pathogenic mechanism
in atherosclerosis.
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Atherosclerosis as an Inflammatory Disease
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The view that atherosclerosis is an inflammatory disease has
become
increasingly prevalent in recent years.
25
Consequently, interest
has accelerated in the mechanisms that cause
localization of
monocytes and T cells in the arterial wall. Emphasis
has been
on the expression by endothelial cells of leukocyte adhesion
molecules
and on chemotactic proteins and factors that facilitate the
recruiting,
expanding, and sustaining of the monocyte/macrophage
population.
Adherence of monocytes to arterial endothelium in
lesion-prone
areas (areas of low shear stress) was one of the first
changes
noted after cholesterol feeding was begun in experimental
animals.
26 This localization was subsequently shown to be
associated with
the expression by the endothelial cells to which the
leukocyte
is attached of an adhesion molecule that was first identified
as
atherosclerosis-related leukocyte adhesion molecule, or
athero-ELAM.
27 This molecule was the rabbit equivalent of
vascular cell adhesion
molecule-1 (VCAM-1) in humans and other species.
A possible
relation between VCAM expression and oxidized LDL was
established
when an important component of this modified lipoprotein,
lysophosphatidylcholine,
was shown to stimulate VCAM expression in
vitro.
28 Subsequently,
modified LDL was also shown to
stimulate the chemokine, monocyte
chemotactic protein-1
(MCP-1).
29 Modified LDL also has been
shown to stimulate
the production of monocyte colony stimulating
factor
(mCSF).
30 Thus, in atherosclerosis the major mechanisms
for
recruiting and sustaining leukocyte populations into the vessel
wall
have been associated with the modifications of LDL, one of the
most
important of which is oxidation. These data do not, however,
prove
a direct causal relation between oxidized LDL and the
recruitment of
inflammatory cells into atherosclerotic lesions.
Nonetheless, the
presence of oxidized LDL in human atherosclerotic
lesions raises the
general issue that signals emanating from
abnormal oxidative metabolism
in the artery might be important
in eliciting the inflammatory
response.
Recent evidence suggests that the molecular link between hyperlipidemia
and the recruitment of inflammatory cells into the atherosclerotic
arterial wall may be the metabolic stress imposed on the endothelium
and the resultant excessive production of oxygen free
radicals.31 32 Aortas from rabbits that had been fed a
high cholesterol diet for several weeks produced severalfold more
oxygen free radicals than did control aortas (Fig 1).
Furthermore, removal of the endothelium resulted in reduction of free
radical production, suggesting that the endothelium is a major source
of the reactive oxygen species in this model. This oxygen free radical
production had obvious functional consequences because defective
endothelium-dependent relaxation in these vessels could
be restored with antioxidants33 or by decreasing free
radical production by returning the animals to their normal
low-cholesterol diet.31 In aggregate these data were
consistent with the hypothesis that the abnormal redox state in the
arterial wall may be a fundamental metabolic feature of atherosclerosis
that is a major contributor to disordered control of vasomotor tone in
coronary artery disease, as alluded to above.

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Figure 1. Bar graph shows oxygen free radical
production by aortas with or without endothelium (Endo) from rabbits
with or without a high-cholesterol diet (Cholest-Fed). Oxygen free
radical production was estimated by lucigenin chemiluminescence.
Endothelium removal in a normal artery increases free radical
production, suggesting that normal endothelium may serve an antioxidant
role. Cholesterol feeding is associated with a severalfold increase in
O2- production in intact aortas. In contrast
with the normal artery, endothelium removal in aortas taken from
hypercholesterolemic animals is associated with a decrease in
O2- production, suggesting that
hypercholesterolemia results in a striking increase in free radical
production by the endothelium. Data are mean±SEM. *P<.05
for normal vessels with and without endothelium (paired t
test); **P<.001 for hypercholesterolemic vs normal vessels
with endothelium (unpaired t test); P<.05 for
hypercholesterolemic vessels with vs without endothelium (paired
t test). (From Ohara et al31 by copyright
permission of The Society for Clinical Investigation.)
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Recently, a relation between oxidative stress in the arterial wall (in
particular, the endothelium) and the development of the inflammatory
response has been clarified. The stimulation by cytokines such as
interleukin-1 (IL-1) of the expression of VCAM-1 by human endothelial
cells is mediated by redox-sensitive control mechanisms.34
The redox-sensitive nature of this gene regulation was determined by
the use of antioxidants that are active intracellularly. As shown in
Figs 2 and 3, the antioxidant pyrolidine
dithiocarbamate (PDTC) inhibited the IL-1induced endothelial
expression of mRNA for VCAM-1 and was as effective as a monoclonal
antibody against the VCAM-1 counterligand very late antigen-4 (VLA-4)
in inhibiting binding of Molt-4 cells, which express VLA-4.

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Figure 2. Blots show that induction of human umbilical vein
endothelial (HUVE) cell vascular cell adhesion molecule-1 (VCAM-1) mRNA
by interleukin (IL)-1ß is selectively inhibited by the antioxidant
pyrolidine dithiocarbamate (PDTC). After pretreatment for 30 minutes
with 50 µmol/L PDTC, HUVE cells were exposed to IL-1ß (10 U/mL) in
the continuous presence of 50 µmol/L PDTC. Total RNA was isolated and
20 µg size fractionated by denaturing 1.0% agarose-formaldehyde gel
electrophoresis, transferred to nitrocellulose, and hybridized to
either 32P-labeled human VCAM-1specific (A),
E-selectinspecific (B), or intracellular adhesion molecule-1
(ICAM-1)specific (C) cDNA and visualized by autoradiography. Lane 1,
0 hour; lanes 2, 4, 6, and 8, IL-1ß alone for 2, 4, 8, and 24 hours,
respectively; lanes 3, 5, 7, and 9, IL-1ß with PDTC for 2, 4, 8, and
24 hours, respectively. Data are consistent with a selective
redox-sensitive mechanism controlling VCAM-1 mRNA expression. (From
Marui et al34 by copyright permission of The Society for
Clinical Investigation.)
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The inhibition of VCAM-1 expression by PDTC appears to occur at the
level of gene transcription.34 Constructs of the VCAM-1
gene promoter were connected to the gene encoding for the enzyme
chloramphenicol acetyltransferase (CAT), which provides a readout of
promoter activation. These constructs were transfected into endothelial
cells for assessment of transcriptional control mechanisms. CAT
activity was found to be stimulated by IL-1 and inhibited by PDTC,
suggesting that a redox-sensitive mechanism controls transcription of
the VCAM-1 gene. A clue to the potential identity of the protein
factors controlling transcription was the presence in the VCAM-1 gene
promoters of consensus binding sites for the protein nuclear factor
kappa B (NF
B). NF
B represents a family of so-called
transcription factors that are present in the cytoplasm and
translocate to the nucleus and bind to gene promoters when
activated.35 NF
B proteins were present in the
nuclei of IL-1stimulated endothelial cells, as reflected in their
binding to NF
B sequences from the VCAM-1 promoter.34
This translocation to the nucleus was inhibited by PDTC. Oxidized LDL
also stimulated VCAM-1 expression in endothelial cells by this
mechanism (unpublished data, 1994). Moreover, the redox-sensitive
control mechanism was specific for VCAM-1: other endothelial leukocyte
adhesion molecules (eg, E-selectin and intracellular adhesion
molecule-1 [ICAM-1]) were not regulated in this manner. Thus, certain
details of the molecular link between hyperlipidemia and the
recruitment of inflammatory cells into the arterial wall are becoming
understood. The current hypothesis is that hyperlipidemia induces an
oxidative stress on the endothelium that leads to the production of
oxygen radical species that stimulate VCAM-1 expression, contributing
to monocyte and lymphocyte recruitment.36
As alluded to previously, other molecules such as mCSF and MCP-1 that
are involved in the recruiting and sustaining of the
monocyte/macrophage population also appear to be regulated by
redox-sensitive mechanisms.37 This suggests that the
pathogenesis of atherosclerosis reflects in part the stimulation in the
endothelial cell of a set of redox-sensitive genes by oxygen free
radicals. Parenthetically and as noted, this free radical production
also probably accounts for the defective
endothelium-dependent vasodilation characteristic of
atherosclerotic vessels. Thus, a certain mechanistic unification theory
appears to be developing.36
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The Effects of Hypertension on the Arterial Wall
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The pathogenesis of hypertension is a multifactorial process
that
involves the interaction of genetic and environmental factors.
In
varying degrees, abnormalities of volume regulation, enhanced
vasoconstriction,
and remodeling of the arterial wall (decreasing lumen
diameter
and increasing resistance) contribute to the development of
hypertension.
38 Various abnormalities in ion transport
have been described
in subsets of hypertensive individuals and in
experimental models.
These generally involve changes in sodium,
calcium, and/or proton
fluxes or concentrations. These changes in
electrolyte metabolism
enhance contractile response and hypertrophy and
proliferation
of vascular smooth muscle cells. Growth and hypertrophy
of the
vessel wall in a small artery are illustrated in Fig 4
. Increases
in blood pressure cause ongoing adaptive
responses in the microvasculature.
The effects of blood pressure are
also exhibited in larger arteries.
In Fig 5
, a renal
artery shows reduplication of the internal
elastic lamina with
hypertrophy of the blood vessel that encroaches
on the lumen. The
increased growth response of vascular smooth
muscle is one of the
characteristics of atherosclerosis in large
arteries. Thus, increased
vascular smooth muscle cell growth
is another common feature in the
pathogenesis of both atherosclerosis
and hypertension. The growth of
vascular smooth muscle is controlled
to an important extent by the
endothelium.
4 The normal endothelium
appears to exhibit an
inhibitory influence on vascular smooth
muscle cell growth.
Dysfunctional endothelium in either atherosclerosis
or hypertension may
contribute to or permit vascular smooth
cell growth, which contributes
to narrowing of the lumen.

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Figure 4. Diagram shows effect of hypertension on smooth
muscle cells. Smooth muscle cells grow either by hyperplasia (increase
in number) or hypertrophy (increase in mass). In hypertensive animals,
changes in smooth muscle mass in large vessels appears to be caused by
hypertrophy, often with endoreplication of DNA that results in a
greater-than-normal diploid content of the DNA. In arterioles, however,
smooth muscle cell mass changes appear to be caused by a true increase
in cell number. (From Alexander et al.39 )
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Figure 5. Photomicrograph shows fibroelastic hyperplasia in a
proximal renal interlobular artery from a patient with long-standing
essential hypertension. As a consequence of this ongoing benign
condition, there is marked reduplication (splitting) of the internal
elastic lamina, marked smooth muscle hypertrophy of the media, mild
medial fibrosis, and intimal thickening. (From Alexander et
al.39 )
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Another effect of medial thickening (whether from hypertrophy and
hypertension or from atherosclerosis) is to increase the distance
required for diffusion of oxygen from the lumen. A decrease in
PO2, in turn, would result in
incomplete oxidation and probably lead to increased concentrations of
free radicals and abnormalities of the redox state.40 41
This oxygen radical formation would contribute to tissue damage and
lipid oxidation, with many of the implications discussed above.
There is increasing evidence that hypertension, like hyperlipidemia,
induces oxidative stress in the arterial wall. It has even been
suggested that superoxide anions might trigger the development of
hypertension in some models, presumably by inactivating
endothelium-derived nitric oxide and thus mitigating
this important vasodilator mechanism.42 A fusion protein
was developed consisting of human copper/zinc superoxide dismutase
(SOD) and a C-terminal basic peptide that would provide high affinity
for heparans on endothelial cells. SOD targeted to the endothelium
would dismutate oxygen free radicals to H2O2.
This SOD fusion protein bound vascular endothelial cells when injected
intravenously and localized within the vessel wall, reducing blood
pressure in spontaneously hypertensive rats but not normal controls
(Fig 6). Blood pressure was also reduced by xanthine
oxidase inhibitors. These observations suggest that oxygen free
radicals may be important in the pathogenesis of hypertension in this
model and that xanthine oxidase may be one potential source of the
oxygen free radicals. An inferred mechanism of blood pressure elevation
here would be the destruction of nitric oxide by excessive production
of oxygen free radicals, although this has not been demonstrated in
this model.

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Figure 6. Line graph shows effect of a superoxide dismutase
(SOD) fusion protein (HB-SOD) targeted to the endothelium on blood
pressure of spontaneously hypertensive rats (SHR) and normal rats.
Blood pressure was determined in the tail artery of conscious rats
using a programmable sphygmomanometer. With rats under light ether
anesthesia, either SOD (open symbols) or HB-SOD (closed symbols) was
administered (25 mg/kg IV) to SHR (circles) and normal rats (squares).
Data show mean±SD derived from 10 to 16 experiments. Arrow shows time
of SOD or HB-SOD injection. Thus, SOD that is targeted to the arterial
wall lowers blood pressure, suggesting that vascular free radical
production contributes to hypertension in this model. (From Nakazono et
al.42 )
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Additional data in other models of hypertension support the notion that
oxygen free radicals contribute to either the causes or consequences of
hypertension.43 Infusion of SOD in rats in which
hypertension was induced by the administration of systemic
norepinephrine shifted the norepinephrineblood pressure response
curves to the right. There was also improved survival in all of the
SOD-treated rats, a result consistent with the possibility that oxygen
free radicals produced by the arterial wall compromise vascular
structural integrity in this model. These data are consistent with the
possibility that this model is associated with increased production of
oxygen free radicals that destroy endothelium-derived
nitric oxide and contribute to hypertension. This same group has shown
that acute hypertension caused by experimental acute brain injury or by
pressor agents is associated with abnormalities of cerebral arterioles,
including the development of endothelial lesions and increased
permeability that is thought to result from enhanced production of free
radicals.43 44 45 46 47 Similar conclusions have been reached from
studies on intestinal microvascular damage in a rat model of acute
angiotensin IIinduced hypertension.48
Additional evidence that hypertension induces an oxidative stress on
the arterial wall comes from a rabbit suprarenal aortic coarctation
model of hypertension. Here, antioxidant defense enzymes related to the
generation of reduced glutathione and thiobarbituric acidrelated
substances (TBARS), formed when oxygen radicals interact with fatty
acids, were increased in the suprarenal but not in the infrarenal
aortic segment.49
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Hypertension and Atherosclerosis May Act Together to Enhance
Arterial Oxidative Stress
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The evidence reviewed here suggests that atherosclerosis and
hypertension
each may enhance the oxidative stress of the arterial
wall.
One might expect additive effects from the presence of both
conditions,
and indirect evidence supports this notion. In rabbits,
hypertension
and hyperlipidemia each enhance arterial expression of
antioxidant
scavenger enzymes. The presence of both conditions is an
even
more potent stimulus, suggesting that through a common mechanism
both
conditions enhance the oxidative stress of the arterial
wall.
41 Additional provocative evidence supporting the
concept that
hypertension and atherosclerosis have certain common
physiological
mechanisms comes from observations in cholesterol-fed
monkeys;
here, hypertension sustained coronary artery plaque
progression
despite the return of cholesterol levels toward normal with
dietary
manipulation.
50
Chobanian51 has called attention to and summarized
similarities in the effects of hypertension and atherosclerosis on the
arterial wall. The argument presented above suggests that oxidative
stress is a manifestation common to both conditions. The mechanistic
data showing that monocyte recruitment mechanisms involve
redox-sensitive steps have been previously summarized and would lead
one to predict that hypertension per se, even in the absence of the
metabolic stress of hyperlipidemia, might be associated with increased
recruitment of mononuclear cells into the arterial wall. In fact, this
appears to be the case. Hypertension in animal models is associated
with leukocyte adhesion, macrophage accumulation, smooth muscle cell
migration and proliferation, and intimal thickening.51 52 53
Lipid accumulation in foam cells and formation of atherosclerotic
plaque are generally not observed if plasma lipoproteins are
low.54 Thus, one reason that hypertension facilitates the
development and progression of atherosclerosis may be that it
oxidatively stresses or injures the endothelium, resulting in
activation of redox-sensitive mechanisms that recruit mononuclear
leukocytes into the arterial wall.
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Summary and Conclusions
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Hypertension and hyperlipidemia exert many similar effects on
the
arterial wall. The increase in oxidative stress, a mechanism
common to
both conditions, may activate genes involved in generating
an
inflammatory response that, in the presence of hyperlipidemia,
leads to
the formation of atherosclerotic plaque (see Fig 7
).
There
is a great deal of interest in the use of antioxidants in the
treatment
of atherosclerosis. The possibility that members of this
class
of compounds might also ameliorate hypertensive vascular injury
deserves
further investigation.

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Figure 7. Flow chart shows mechanism of synergism of
hypertension and hyperlipidemia in the pathogenesis of atherosclerosis.
When hypertension accompanies hyperlipidemia, the two act together to
trigger a cascade. Increased production of oxygen free radicals leads
to increased transcription of redox-sensitive genes, which increases
expression of vascular cell adhesion molecule-1 (VCAM-1) by the
endothelium, resulting in increased recruitment of monocytes. Both
hypertension and hyperlipidemia cause oxidative stress and oxygen free
radical production by the arterial wall. By activating redox-sensitive
transcriptional control mechanisms in the endothelium, a set of genes
controlling monocyte recruitment into the arterial wall is activated.
Atherosclerosis and foam cell formation occur only in the presence of
hyperlipidemia. A synergistic reaction between hypertension and
hyperlipidemia, causing or enhancing atherosclerosis, may occur because
both states are associated with a common causal mechanism: induction of
alterations in vascular redox state. mCSF indicates monocyte colony
stimulating factor; MCP-1, monocyte chemotactic protein-1.
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Acknowledgments
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This work was supported in part by Program Project Grant No.
PO1HL-48667
in Vascular Biology from the National Heart, Lung, and
Blood
Institute of the National Institutes of Health, Bethesda, Md.
The
author also wishes to thank Kate W. Harris for invaluable
assistance in
the preparation of this manuscript.
 |
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