© 1999 American Heart Association, Inc.
Review |
Oxidative Stress as a Regulator of Gene Expression in the Vasculature
From AtheroGenics, Inc (C.K., R.M.M.), Alpharetta, and Division of Cardiology (R.M.M.), Department of Medicine, Emory University School of Medicine, Atlanta, Ga.
Correspondence to Russell M. Medford, MD, PhD, AtheroGenics, Inc, 8995 Westside Pkwy, Alpharetta, GA 30004. E-mail rmedford{at}atherogen.com
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Abstract |
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 Top Abstract IntroductionEC Dysfunction and...Oxidative Signaling and Vascular...Atherogenic Risk Factors as...Redox-Sensitive Transcriptional...Redox Modulation of...ConclusionReferences |
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Abstract—Oxidative stress and the production of intracellular reactive oxygen species (ROS) have been implicated in the pathogenesis of a variety of diseases. In excess, ROS and their byproducts that are capable of causing oxidative damage may be cytotoxic to cells. However, it is now well established that moderate amounts of ROS play a role in signal transduction processes such as cell growth and posttranslational modification of proteins. Oxidants, antioxidants, and other determinants of the intracellular reduction-oxidation (redox) state play an important role in the regulation of gene expression. Recent insights into the etiology and pathogenesis of atherosclerosis suggest that this disease may be viewed as an inflammatory disease linked to an abnormality in oxidation-mediated signals in the vasculature. In this review, we summarize the evidence supporting the notion that oxidative stress and the production of ROS function as physiological regulators of vascular gene expression mediated via specific redox-sensitive signal transduction pathways and transcriptional regulatory networks. Elucidating, at the molecular level, the regulatory processes involved in redox-sensitive vascular gene expression represents a foundation not only for understanding the pathogenesis of atherosclerosis and other inflammatory diseases but also for the development of novel therapeutic treatment strategies.
Key Words: redox • gene expression • atherosclerosis • oxidation • signaling
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Introduction |
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TopAbstractIntroductionEC Dysfunction and...Oxidative Signaling and Vascular...Atherogenic Risk Factors as...Redox-Sensitive Transcriptional...Redox Modulation of...ConclusionReferences |
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Eukaryotic cells have evolved highly elaborate mechanisms to rapidly respond to changes in their environment by altering the expression of genes. Various forms of cellular stress constitute primary signals that are transduced into the cytoplasm and ultimately alter the expression of specific genes in the cell nucleus. One such form of cellular stress is the production of oxygen free radicals or reactive oxygen species (ROS). Historically, ROS have been implicated in a variety of distinct cellular stresses including heat shock, ionizing and UV irradiation, and a variety of oxidizing pollutants such as tobacco smoke and ozone. In addition, inflammatory cells such as neutrophils and macrophages have evolved a mechanism to use ROS in host defense. These cells release intracellular hydrogen peroxide (H2O2) and superoxide in response to invading organisms in large amounts that are generally toxic to the invading microorganisms. Recently, however, many other cell types, such as fibroblasts, endothelial cells (ECs), and smooth muscle cells (SMCs), have been shown to produce ROS at relatively low levels in response to cellular "activation" signals. In contrast to the view that oxidative stress and ROS are damaging to the cell, it has been proposed that ROS in these cells play a role as second messengers to regulate signal transduction pathways that ultimately control gene expression and posttranslational modifications of proteins. ROS have been implicated in a variety of diseases, including Alzheimer disease, cancer, and vascular diseases such as atherosclerosis. The focus of this review is to summarize the current literature supporting the notion that ROS in the vasculature function as physiological regulators of gene expression by modulating specific redox-sensitive signal transduction pathways and transcriptional regulatory events.
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EC Dysfunction and Atherosclerosis |
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TopAbstractIntroductionEC Dysfunction and...Oxidative Signaling and Vascular...Atherogenic Risk Factors as...Redox-Sensitive Transcriptional...Redox Modulation of...ConclusionReferences |
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Atherosclerosis is a complex, multifactorial disease in which the cellular and molecular mechanisms contributing to the disease process are poorly defined. Recent insights into the pathogenesis of atherosclerosis suggest that it may be viewed as a chronic inflammatory disease with an underlying abnormality in redox-mediated signals in the vasculature.1 2 3 In a normal, healthy state, the vessel wall is composed of a single-cell–thick EC lining that exhibits intimate contact with the medial layer of vascular SMCs (VSMCs). Encircling this is the adventitial layer consisting of a dense matrix of connective tissue. As such, the EC is optimally situated at the interface between the circulating blood and the vessel wall to serve as a sensor and transducer of signals within the circulatory microenvironment. Therefore, the EC is integral in maintaining the homeostatic balance of the vessel through the production of factors that regulate vessel tone, coagulation state, cellular proliferative response, and leukocyte trafficking. In vascular disease, however, EC dysfunction occurs when the cell loses its ability to maintain the normal homeostatic balance, ultimately leading to impairment in vasorelaxation and increased adhesiveness of the EC lining for circulating inflammatory cells.3
EC dysfunction is central to the pathogenesis of atherosclerosis. Although the precise cellular and molecular processes involved in the pathogenesis are unknown, atherosclerosis is generally viewed as a chronic inflammatory disease of the arterial intima characterized by the formation of the atherosclerotic plaque, which is a focal accumulation of mononuclear leukocytes, SMCs, lipids, and extracellular matrix components.3 4 One of the earliest detectable events in the generation of atherosclerosis is the infiltration of inflammatory cells to discrete segments of the arterial wall and their transformation into lipid-laden macrophages (foam cells). The initial recruitment of leukocytes into the lesion is mediated by an increased gradient in chemotactic factors released from the endothelium or SMCs by various inflammatory stimuli. Accumulating evidence suggests that these inflammatory signals and other "proatherogenic" stimuli result in the production of ROS within the endothelial microenvironment. As discussed below, several lines of investigation suggest that the production of ROS and the resultant oxidative stress play a key role in mediating the pathologic manifestations of EC dysfunction associated with atherosclerosis.
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Oxidative Signaling and Vascular Inflammatory Gene Expression |
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TopAbstractIntroductionEC Dysfunction and...Oxidative Signaling and Vascular...Atherogenic Risk Factors as...Redox-Sensitive Transcriptional...Redox Modulation of...ConclusionReferences |
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Hyperlipidemia, diabetes, hypertension, and smoking are well-established risk factors for the development of atherosclerosis. However, the molecular and cellular mechanisms linking these diverse risk factors to a common pathologic mechanism are unclear. A current hypothesis suggests that modulation of the expression of a selective set of vascular inflammatory genes by intracellular oxidative signals may provide a molecular mechanism linking these seemingly diverse risk factors with the early pathogenesis of atherosclerosis (Figure 1
).5 6 As such, various
proinflammatory or prooxidant stimuli associated with these risk
factors may directly stimulate or sensitize vascular cells to generate
ROS. These ROS and/or their modified target biomolecules (ie, oxidized
LDL) then serve as true second-messenger coupling molecules to transmit
these extracellular signals to elevated expression of atherogenic gene
products such as adhesion molecules and other vascular inflammatory
gene products. The induced expression of these gene products
thus promotes the infiltration of monocytes into the vessel wall and
the release of additional proinflammatory signals. Accordingly, this
positive feedback loop would serve to potentiate the local inflammatory
response and EC dysfunction. Conversely, chemical or cellular
antioxidants would protect vascular cells against oxidative stress by
scavenging ROS generated from the inflammatory stimuli and altering the
oxidative milieu or by directly modulating redox-sensitive signaling
pathways and blocking atherogenic gene expression.
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Consistent with this hypothesis is the observation that the
expression of vascular inflammatory gene products such as vascular
cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant
protein-1 (MCP-1) by diverse proinflammatory stimuli occurs through a
redox-sensitive mechanism involving the redox-regulated transcription
factor nuclear factor-
B (NF-B).7 8 9 Thiol
antioxidants such as pyrrolidine dithiocarbamate (PDTC) and
N-acetylcysteine (NAC) and other chemically distinct
antioxidants (our unpublished observations, 1998) inhibit
cytokine-inducible expression of both VCAM-1 and MCP-1 in ECs.
Thus, ROS may act as specific regulators in the signal transduction
network to relay environmental and physical signals generated at the
cell membrane to nuclear regulatory signals resulting in modulation of
inflammatory gene expression. In the following sections, we will
discuss the current state of the literature with respect to
understanding the following: (1) the association of selected
atherogenic risk factors with oxidative stress, (2) specific
transcriptional regulatory factors and signaling events modulated by an
altered redox environment in the vasculature, and (3) the functional
implications of redox-sensitive modulation of gene expression in the
vasculature with respect to the pathogenesis of
atherosclerosis.
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Atherogenic Risk Factors as Mediators of Oxidative Stress |
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TopAbstractIntroductionEC Dysfunction and...Oxidative Signaling and Vascular...Atherogenic Risk Factors as...Redox-Sensitive Transcriptional...Redox Modulation of...ConclusionReferences |
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A variety of pathophysiological processes involved in atherosclerosis such as hyperglycemia, hypertension, hyperlipidemia, and local hemodynamic stresses are known to mediate elevated levels of ROS in the vasculature. However, mammalian cells are protected from ROS by antioxidant defense mechanisms such as the enzymes catalase, superoxide dismutase (SOD), and glutathione peroxidase (GPx). When the normal redox homeostasis of the cell is upset and the rate of formation of ROS exceeds the capacity of the antioxidant defense system, a condition of oxidative stress occurs. Despite the experimental evidence implicating redox processes and oxidative stress in the pathogenesis of atherosclerosis, little is known about the relative role of each of the potential sources for ROS production in the vasculature. It is beyond the scope of this review to provide a detailed examination of the sources and mechanisms involved in ROS production; this topic has been reviewed in detail elsewhere (References 10 and 1110 11 and references therein). Rather, we will only briefly discuss the contribution of selected atherogenic risk factors to cellular redox control and the involvement of selected sources of ROS in the vasculature as they relate to their potential involvement in mediating redox-sensitive gene expression.
There are a variety of intracellular sources for free radicals and ROS
that have been identified (Table). These include, but are not limited
to, normal products of mitochondrial respiration, NADPH oxidase,
nitric oxide (NO) synthases, cyclooxygenases,
lipoxygenases, cytochrome P-450
monooxygenase, and xanthine oxidase.10 11 Via
the action of these enzymatic sources and the autoxidation of various
soluble cellular biomolecules, eukaryotic cells
continuously produce ROS, including superoxide anion
(O2·-), hydrogen
peroxide (H2O2), and
hydroxyl radicals (OH·). The literature supporting the involvement of
various sources of ROS and the nature of individual reactive species
has been generalized from many different in vitro and in vivo systems.
The role of any of these sources as they relate to ROS
production is not well established for cell types of the
vasculature. Furthermore, the relative contribution of any of these to
the pathogenesis of diseases of the vasculature is not well
established, and their relative role will likely vary with cell type
and physiological state of the cell.
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Although the identity of the ROS-generating systems in the vasculature is not clear, evidence suggests that NADPH oxidase-like activity appears to be a contributing source of ROS via the generation of superoxide anion in both cultured ECs12 13 and VSMCs,14 as well as in intact aortas.15 Molecular and enzyme inhibition studies suggest that the enzyme responsible for superoxide production in the vasculature is similar to the phagocyte-type NADPH oxidase13 16 17 18 19 ; however, the precise molecular identity of the oxidase is not known. Furthermore, given that the lucigenin assay (which is routinely used to measure NADPH production of superoxide) has been a subject of controversy because of its ability to spontaneously generate superoxide under certain assay conditions, care should be taken in drawing conclusions about the role of NADPH in superoxide production in studies using this assay.
Cytokines and growth factors such as tumor necrosis factor-
(TNF-), interleukin (IL)–1ß, angiotensin II (Ang II),
and interferon-
activate membrane-bound NADPH oxidase to
produce superoxide in ECs.12 14 19 20 Diphenylene
iodonium, an inhibitor of NADPH oxidase, has been shown to
abrogate superoxide production in response to TNF- in
ECs.21 The notion that ROS generated via an NADPH oxidase
activity may function as signaling molecules to modulate vascular gene
expression is supported by the observation that NADPH oxidase
inhibitors block cytokine-induced VCAM-1 and
intercellular adhesion molecule-1 (ICAM-1) gene expression in human
aortic ECs21 and attenuate Ang II–mediated activation of
VCAM-1 and MCP-1 in VSMCs.22 Consequently, the generation
of ROS via NADPH oxidase activity in response to proinflammatory
stimuli may regulate the expression of a variety of redox-sensitive
genes in the vasculature.
The ROS NO is produced by a variety of cell types, including ECs,
macrophages, SMCs, and fibroblasts and has been shown to be an
important factor in the regulation of many biological responses. NO
produced by the endothelium modulates vasomotor tone,
inhibits platelet aggregation, and inhibits SMC proliferation,
properties that have been shown to be antiatherogenic.23
Several studies have demonstrated NO regulation of vascular
inflammatory gene expression, including that of
VCAM-124 25 and MCP-1.26 27 Furthermore,
several studies have demonstrated that NO levels modulate the activity
of cytokine-activated NF-B in
ECs,24 27 28 thus providing a potential mechanism for NO
suppression of vascular gene expression. NO may modulate gene
expression by altering the intracellular oxidative environment. On the
basis of the cell type or concentrations present, NO has been shown
to both augment29 30 and inhibit31 32 oxygen
radical–mediated tissue damage and lipid peroxidation. NO has been
shown to (1) reduce superoxide generation,26 33 (2)
inhibit oxidation of LDL and delay the formation of lipid
peroxides,34 and (3) redirect the reactivity of partially
reduced oxygen species.35 On the other hand, NO can react
with superoxide to produce peroxynitrite anion
(ONOO-), which is a potent
oxidant.36 In fact, although ONOO-
itself is a highly reactive free radical, it is possible that
ONOO- could subsequently nitrosylate sulfhydryl
groups to form S-nitrosothiols.37
Therefore, NO exhibits a dual redox function that is based on its
interaction with other ROS. Thus, through direct modulation of
intracellular oxidative stress, NO can modulate signaling pathways
(such as those involved in NF-B activation) and regulate the
expression of vascular inflammatory genes such as VCAM-1 and MCP-1.
Hypertension and Ang II
Hypertension is an established risk factor for the development of
vascular disease, and both clinical and experimental evidence support a
potential role of the renin-angiotensin system in
contributing to the pathogenesis of hypertension-associated
atherosclerosis.6 Recent studies have
supported a role for Ang II in the generation of oxidative stress in
the vasculature via the induction of superoxide via NADPH
oxidase.14 In addition, Ang II has been shown to stimulate
the increase of both MCP-1 and VCAM-1 mRNA expression in rat
aortas.38 In these experiments, the increased expression
of both VCAM-1 and MCP-1 by Ang II could be blocked by NADPH oxidase
inhibitors and catalase, suggesting that NADPH oxidase may
be contributing to oxidative stress and regulation of vascular
inflammatory genes via the generation of
H2O2. Thus, Ang II, through
the formation of oxidative stress and increased levels of
proinflammatory genes in the vessel wall, may serve as a molecular link
between hypertension and the pathogenesis of
atherosclerosis.
Hyperglycemia
Other established risk factors for the development of vascular
disease are complications related to diabetes as a consequence of
hyperglycemia. Diabetes-associated hyperglycemia produces an
intracellular oxidative stress that leads to vascular
dysfunction.39 It has been documented that relatively high
concentrations of glucose stimulate superoxide generation and enhance
cell-mediated LDL peroxidation in ECs.40 41 In addition,
incubation of ECs with high concentrations of glucose result in an
increased activation of the redox-sensitive transcription factor
NF-B,42 suggesting that hyperglycemia may
activate endothelial gene expression via
activation of NF-B.
Advanced glycation end products (AGEs) are posttranslational
modifications of cellular proteins believed to play a role in the
vascular complications associated with diabetes.43
Interaction of AGEs with cell surface receptors (RAGEs) has been shown
to generate ROS, decrease the levels of reduced glutathione, and
activate NF-B.44 45 Chronic AGE accumulation in
animals promotes VCAM-1 expression and formation of atherosclerotic
lesions in the absence of hyperglycemia.46 In addition,
AGE-induced expression of VCAM-1 and
monocyte/endothelial interactions can be blocked by
antioxidants.46 These observations suggest that pathogenic
processes associated with diabetes may result in modulation of the
intracellular redox state and expression of redox-sensitive
inflammatory genes in the vessel wall.
Modified LDL
One of the earliest events in atherosclerosis is
the oxidative modification of lipoproteins (in particular, LDL) in the
vessel wall. The role of oxidatively modified LDL (oxLDL) as an
important oxidative signal in the pathogenesis of
atherosclerosis has been well
established.5 47 oxLDL is a complex structure consisting
of several chemically distinct oxidants. oxLDL alters the intracellular
redox status of the cell in part through the generation of
superoxide48 and has been implicated as an important
prooxidant signal in the pathogenesis of
atherosclerosis.5 Although controversial,
several studies suggest that oxLDL or fatty acid hydroperoxides (one of
the more abundant components of oxLDL) act as prooxidant signals to
regulate monocyte adhesion, vascular gene expression such as ICAM-1 and
VCAM-1,49 50 and redox-sensitive transcriptional factors
such as activator protein-1 (AP-1)51 and
NF-B.52 53 54 Although the concentrations of oxLDL used
in some of these studies may be greater than that predicted to occur in
circulating serum, it has been suggested that in vivo, LDL accumulates
and is oxidized in a localized microenvironment that is relatively
sequestered from plasma antioxidants.5 55 In contrast to
the effects of oxLDL, nonmodified (native) LDL has also been shown to
induce adhesion molecule expression on ECs.56 57
Therefore, the role of oxidation of the LDL particle and the exact
nature of the chemical oxidants in mediating
endothelial/leukocyte adhesion is an area for
additional investigation.
Also controversial is the enzymatic source of LDL oxidation. It has
been proposed that cellular lipoxygenases (LOs) may
mediate LDL oxidation and the formation of fatty acid hydroperoxides in
several cell types. Increased levels of 15-LO activity have been
detected in atherosclerotic lesions in rabbit and human aorta compared
with normal arteries.58 59 Furthermore, transient
overexpression of 15-LO enhances TNF-–induced VCAM-1
expression,60 and 5-LO inhibitors blocked
IL-1ß–induced VCAM-1 expression in ECs.61 Together,
these studies suggest a role for oxLDL as a prooxidant signal that
modulates the expression of redox-sensitive inflammatory gene
products. As of yet, the exact nature of the cellular signals that
lead to the generation of oxidized lipids are not known, although LOs
likely play a key role.
Hemodynamic Forces
Vascular ECs are constantly subjected to the influence of
hemodynamic forces including shear stress imposed by
blood flow. The localization of atherosclerotic lesions to areas of low
shear stress has led to the hypothesis that local
hemodynamic forces may contribute to the focal nature
of early atherosclerotic lesion development.62 The effects
of fluid shear stress on endothelial biology and gene
expression have been extensively studied (for review, see References 63
and 6463 64 ), and one of the biological effects is alteration of
EC/leukocyte interactions. This altered adhesivity of leukocytes for
the EC is caused, at least in part, by the regulation of the adhesion
proteins ICAM-1 and VCAM-1.
Several studies have demonstrated that increased blood flow and fluid shear stresses alter the EC redox state and redox-sensitive gene expression.65 66 67 68 69 Laurindo et al65 provided both ex vivo and in vivo evidence that increases in blood flow lead to increased intracellular free radical release. In these studies, electron paramagnetic resonance spectroscopy was used to show that perfusion of isolated aortas led to increased levels of free radicals only in aortas containing an intact endothelium. This effect was completely blocked by addition of SOD, an antioxidant enzyme that accelerates the conversion of superoxide to H2O2. Similar effects were observed with in vivo–induced changes in blood flow. Hsieh et al67 demonstrated that exposure of ECs to a steady laminar shear stress resulted in an increase in intracellular ROS and expression of the redox-sensitive transcription factor c-fos. These changes were abolished by treatment with the antioxidant NAC or catalase. Similar results were observed by Chiu et al,68 who demonstrated that shear stress–induced elevations of intracellular superoxide levels and ICAM-1 mRNA and promoter activities could by blocked by NAC and SOD.
De Keulenaer et al66 showed that oscillatory shear stress induced the expression of NADH oxidase (a major source of ROS in the vasculature), superoxide, and the redox-sensitive gene heme oxygenase-1 in cultured ECs. These effects could be blocked by pretreatment with the antioxidant NAC. In contrast, application of steady laminar shear induced only a transient increase in NADH oxidase and lower levels of superoxide. The authors suggest that steady laminar shear may induce compensatory antioxidant defense mechanisms by the observed increased expression of SOD, an antioxidant defense enzyme of which the level of expression adapts to changes in oxidative stress. Similar increases in SOD expression by shear stress were observed in human arterial ECs70 and human umbilical vein ECs.71 The notion that steady laminar shear stress may play a protective role in vasculature is supported by the observation that steady unidirectional shear stress decreases the basal and cytokine-induced expression of VCAM-1 in human ECs.72 73 Furthermore, steady laminar shear preconditioned ECs exhibited a reduced synthesis of fatty acid hydroperoxides compared with static control cells (S.E. Varner and R.M. Medford, unpublished observations, 1997).
In addition to the generation of ROS, it is well known that shear
stress is also a potent stimulus for endothelial
synthesis of NO.74 75 This may be caused, in part, by an
increase in EC NOS steady-state mRNA levels71 76 and may
be mediated by activation of c-Src–dependent serine kinase by shear
stress.77 Tsao et al72 have shown that NO
mediates the steady shear stress inhibition of oxLDL and
lipopolysaccharide/TNF-–induced superoxide
production, NF-B activation, VCAM-1 expression, and
endothelial-monocyte adhesion. Therefore, given the
recent evidence that NO may reduce intracellular oxidative
stress,26 33 34 35 elaboration of NO may be one mechanism by
which ECs modulate the level of intracellular oxidative stress and
regulate redox-sensitive gene expression in response to changes in
endothelial shear stresses. Cumulatively, these data
support the notion that differences in EC redox state, which may be
modulated by different types of shear stresses, may contribute to
altered endothelial gene expression and contribute to
the focal nature of atherosclerosis.
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Redox-Sensitive Transcriptional Signaling Pathways |
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TopAbstractIntroductionEC Dysfunction and...Oxidative Signaling and Vascular...Atherogenic Risk Factors as...Redox-Sensitive Transcriptional...Redox Modulation of...ConclusionReferences |
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The notion that oxidative stress can modulate a wide variety of biological processes by coupling signals at the cell surface into long- term changes in gene expression suggests that multiple signaling pathways are involved. Transcription factors are the principal nuclear factors that control gene expression. Modulation of their activity is mediated by signaling pathways that impart posttranslational modification to transcription factors. In this regard, ROS may be defined as true second-messenger molecules that regulate various intracellular signal transduction cascades and ultimately affect transcriptional activity. Indeed, ROS can affect multiple signal transduction pathways upstream of nuclear transcription factors, including modulation of Ca2+ signaling, protein kinase, and protein phosphatase pathways. For comprehensive reviews on oxidant stress and signal transduction, see References 78 through 8078 79 80 .
Ca2+ Signaling
Ca2+ is a widely used second messenger that
regulates a variety of biological processes, including gene expression,
neurotransmission, cell motility, and cell growth. In response to
physiological stimuli at the cell surface, the
intracellular level of Ca2+ rises, and this
elevation elicits the activation of
Ca2+-dependent proteins such as protein kinase C,
Ca2+-calmodulin kinases, and
calmodulin-dependent protein phosphatases (calcineurin).
Oxidants have been shown to stimulate Ca2+
signaling by increasing cytosolic Ca2+
concentration,78 suggesting a possible
physiological role of ROS and oxidative stress in
the regulation of Ca2+-induced signaling in the
vasculature. Increases in intracellular Ca2+ were
detected in response to
H2O2 treatment of
VSMCs,81 and ECs treated with hypoxanthine and
hypoxanthine oxidase (a physiological
oxidant-generating enzyme system)82 and
H2O283 showed a
transient release of Ca2+ from
intracellular stores. Similarly, in rabbit aortic ECs, treatment with
linoleic acid hydroperoxide resulted in a transient increase in
intracellular Ca2+.84 Although the
exact molecular targets of oxidant-mediated Ca2+
signaling are not known, the ability of various oxidants to inhibit the
activity of an ATP-dependent Ca2+
pump85 86 suggests that direct modification of
Ca2+ pumps by oxidants may be one mechanism of
oxidant-mediated Ca2+ signaling. It is also
likely that enhanced Ca2+ transport through
Ca2+ channels is another potential target, given
that the Ca2+ channel blocker
Ni2+ partially inhibits
H2O2-mediated increase in
intracellular Ca2+ in ECs.83 Thus,
evidence exists to suggest the potential involvement of ROS-mediated
Ca2+ flux in early signaling pathways; however,
the exact mechanisms remain to be elucidated.
Protein Phosphorylation
Phosphorylation of proteins is, in most cases, the
penultimate event in the signaling cascade leading to changes in gene
expression. Transcription factors or their interacting proteins are
frequently the direct target of phosphorylation
modifications that either stimulate or inhibit their activity. The
most-well studied classes are the serine/threonine kinase/phosphatases
and tyrosine kinase/phosphatases. It has been estimated that there are
upwards of 2000 distinct protein kinases and 1000 protein phosphatases
in the mammalian genome.87 Therefore, it is not surprising
that experimental evidence is beginning to emerge implicating multiple
protein kinase/phosphatase pathways in redox-mediated signaling
events.
Tyrosine Kinases
Stimulation of tyrosine kinase activity by oxidants or agents that
induce oxidative stress has been observed by a number of laboratories
in a variety of cell types (reviewed in Reference 7878 ). For example,
ionizing radiation and
H2O2, agents that induce
oxidative stress, have been demonstrated to induce tyrosine
phosphorylation events and activate downstream
kinases such as protein kinase C, p56 lck, and
p72raf1.88 89 90 Sundaresan et al91
demonstrated that stimulation of VSMCs by platelet-derived growth
factor transiently increases intracellular
H2O2 production,
resulting in tyrosine phosphorylation, activation of
mitogen-activated protein kinase (MAPK) activity, and
chemotaxis. These effects were blocked by increasing the intracellular
concentration of the free radical scavenging enzyme catalase or by NAC.
These results suggest a direct role for
H2O2 as a
signal-transducing molecule via modulation of a tyrosine
phosphorylation event. Because many growth factor
receptors (such as platelet-derived growth factor) are themselves
tyrosine kinases, these membrane-associated signaling molecules are
well situated to monitor the peroxidation state of lipid bilayers, a
sensitive reflection of cellular redox status. Indeed, it has been
shown that the redox responsiveness of some tyrosine kinase receptors
is ligand independent.92 93
It is not yet clear whether ROS cause direct activation of tyrosine kinase activity or the observed increases in tyrosine phosphorylation are caused by inhibition of tyrosine phosphatase activity by oxidant-mediated signals. Because all tyrosine phosphatases have reactive cysteine residues in their active sites, it has been proposed that inhibition of tyrosine phosphatase activity by oxidants may account for the mechanisms of stimulation of tyrosine phosphorylation by oxidant stimuli.78 In this regard, it has been reported that the oxidizing agents phenylarsine oxide94 and H2O295 96 inhibit tyrosine phosphatase activity. Similarly, PKC-mediated serine/threonine phosphorylation in response to oxidative stress may be the result of inhibition of protein phosphatase 1 and 2A activity, given that thiol oxidation in these phosphatases has been shown to inhibit the enzyme activity.78 Consequently, the activation of a signal transduction pathway in response to oxidative stress may be mediated by inhibitory activities of oxidants at the molecular level.
Mitogen-Activated Protein Kinases
MAPKs play a role in relaying signals from extracellular stimuli
to the cell nucleus, where they are often the ultimate regulatory
proteins in a series of sequential kinase reactions that target
transcription factor modification. The MAPK family consists of the
extracellular signal–regulated kinases (ERK) subgroup, the
stress-activated protein kinase, or c-jun N-terminal kinase
(SAPK/JNK) subgroup, and the p38 MAPK subgroup. One of the
better-characterized functional targets of the MAPK family is the
transient phosphorylation of the transcription factor
complex that regulates the c-fos promoter. Another is the
phosphorylation and subsequent activation (by the
SAPK/JNK family) of the transcriptional activation domain of
c-jun. As discussed below, both c-jun and c-fos are components of the
well-characterized redox-sensitive transcription factor AP-1. Although
not the focus of this review, considerable experimental evidence
supports the notion that changes in the cellular redox state by either
an induction of an oxidative stress or administration of antioxidants
activate signaling pathways involving various members of the
MAPK family.78 97 Although MAPK regulation by ROS and
antioxidants is often demonstrated, it is important to remember that
these kinases are downstream in the signal transduction pathways.
Therefore, it is difficult to assess the direct contribution of ROS on
the modulation of MAPK activity. Redox modulation of their activity may
reflect more direct effects on upstream signaling processes that
ultimately converge on the MAPKs.
Several reports have begun to address the involvement of the MAPK signaling pathway in redox-mediated signaling in the vasculature. Initially, Baas and Berk98 demonstrated that addition of the superoxide-generating agent LY83583 to VSMCs resulted in a concentration-dependent increase in MAPK activity. Various physiological agents believed to play a role in vascular dysfunction, including oxLDL,99 Ang II,100 lactosylceramide (Lac-Cer),101 and linoleic acid and its metabolites,84 have been shown to activate MAPK activity in VSMCs via the generation of intracellular ROS. Ushio-Fukai et al100 demonstrated that Ang II elicited an increase in intracellular H2O2 and a rapid phosphorylation of both p42/44 MAPK and p38 MAPK. Inhibitors of NADPH oxidase and overexpression of catalase blocked Ang II–mediated phosphorylation of p38 MAPK. Also, Lac-Cer, a ubiquitous glycosphingolipid implicated in the proliferation of SMC and found at high concentrations in atherosclerotic plaques, was shown to stimulate endogenous superoxide production in aortic SMCs by activation of NADPH oxidase.101 The increase in superoxide production resulted in activation of the MAPK pathway and ultimately induction of c-fos and cell proliferation. Alteration of the cellular redox status by treatment with the antioxidants PDTC and NAC inhibited Lac-Cer–generated superoxide and blocked the phosphorylation/activation of p44 MAPK. Also, in human umbilical vein ECs, H2O2 activated p38 MAPK activity with an associated marked reorganization of the stress-fiber network associated with the assembly of vinculin to focal adhesions.102 A specific inhibitor of p38 MAPK activity (SB203580) blocked the H2O2-induced microfilament responses, suggesting that p38 MAPK is a critical redox-sensitive pathway functioning in the reorganization of endothelial microfilament network.
Hypoxia and reoxygenation impose 2 extremes of redox stress on cardiac tissue and are principal components of myocardial ischemia and reperfusion. Reperfusion of ischemic tissue is associated with cell injury caused by ROS that are generated by reoxygenation. These ROS cause cell damage directly, by oxidation of cellular components, and also indirectly, by the activation of localized inflammation103 104 105 106 likely via the action of redox-sensitive signaling pathways resulting in increased inflammatory gene expression. Although the signals and pathways that mediate the response of cardiac myocytes to this type of redox stress are unclear, several groups have demonstrated direct effects of hypoxia/reoxygenation in cardiac myocytes on both the SAPK/JNK and p38 MAPK pathways97 107 108 109 110 and have shown that both p38 MAPK and SAPK/JNK activity is strongly attenuated by preincubation of the cells with antioxidants and tyrosine kinase inhibitors.97 Cumulatively, these results implicate unquenched ROS as a stimulus that initiates MAPK signaling pathways in the vasculature and provide a molecular link to physiological stimuli that alter intracellular ROS levels and changes in gene expression and cellular function.
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Redox Modulation of Transcription Factor Activity |
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TopAbstractIntroductionEC Dysfunction and...Oxidative Signaling and Vascular...Atherogenic Risk Factors as...Redox-Sensitive Transcriptional...Redox Modulation of...ConclusionReferences |
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The hypothesis that redox-sensitive signaling pathways regulate vascular inflammatory gene expression suggests that ultimately, specific DNA binding proteins, or transcription factors, will be the target of such a signaling cascade. Transcription factors are central to any discussion of gene regulation, as they are the nuclear components that are modulated by upstream signaling events. By virtue of their ability to interact with very specific DNA sequences (which are unique to each transcription factor) in the regulatory regions of genes, transcription factors serve to modulate not only the magnitude of gene expression, but also the specificity of the signal. This specificity is determined in part by the presence or absence of a binding site in the promoter region of the target gene. Theoretically, redox-sensitive modulation of transcription factor activity can occur via (1) direct oxidative modification of the transcription factor itself by intracellular ROS or (2) posttranslational modifications (ie, phosphorylation/dephosphorylation), by the effects of redox-regulated intracellular signaling cascades. Either mechanism can potentially affect various aspects of transcription factor function, such as subcellular localization, DNA binding properties, and inherent transcriptional activity.
The activity of many eukaryotic transcription factors has
been reported to be modulated by redox changes by one of the above
mechanisms and has been summarized in several excellent
reviews.78 111 112 113 Many of the reported studies
demonstrate changes in the in vitro DNA binding activity of
transcription factors in response to oxidants or reductants. Generally,
highly conserved cysteine residues in the DNA binding regions of these
proteins have been shown to be targets of redox modulation. These in
vitro studies have generally shown that reducing environments increase,
whereas oxidizing conditions inhibit, sequence-specific DNA binding.
However, when intact cells have been used for study, it is generally
observed that oxidizing agents activate and reducing conditions
inhibit transcription factor activity. These observations present
an intriguing paradox and suggest that in vivo more complex regulatory
networks mediated by ROS impart redox control of transcription factor
activity. It is likely that transcription factor activity depends not
only on direct protein modification by intracellular ROS, but also on
posttranslational modifications to the transcription factor as a result
of redox-sensitive signaling pathways. Although redox regulation of
many transcription factors has been documented,113 we will
focus on the 2 most well-characterized transcription factors subject to
redox regulation in the vasculature, NF-B and AP-1, and will discuss
recent evidence implicating the potential role of the peroxisome
proliferator-activated receptor (PPAR) family of
transcriptional activators in oxidative stress.
Redox Regulation of AP-1
NF-B and AP-1 are the most well-studied transcriptional factors
influenced by the cellular redox state.111 113 They have
been implicated in transcriptional regulation of a wide range of genes
involved in cellular inflammatory responses, tissue destruction, and
growth control. Homodimers and heterodimers of members of the c-jun and
c-fos proto-oncogene families constitute the transcription factor AP-1.
At least 3 mammalian Jun proteins (c-Jun, Jun B, and Jun D) and 4 Fos
family members (c-Fos, Fra-1, Fra-2, and Fos B) have been identified
(reviewed in Reference 114114 ). All of the Jun family proteins are capable
of forming homo- and heterodimers that are capable of binding to AP-1
DNA binding sites. Fos proteins do not associate with each other but
are capable of associating with any member of the Jun family to form
stable heterodimers that have higher DNA binding activity than Jun-Jun
homodimers.115 Both the Jun:Jun and Fos:Jun forms of AP-1
bind to a specific DNA sequence (the tissue-type
plasminogen activator–responsive element, TRE)
in promoters of many inducible genes. The promoter for the c-jun gene
contains a TRE and is primarily activated by AP-1 in a positive
autoregulatory fashion.114 116 The promoter for c-fos,
however, does not contain a TRE and thus is not subject to
autoregulation by AP-1.
The activity of AP-1 is controlled by both transcriptional and
posttranslational mechanisms in response to a variety of extracellular
stimuli, including mitogens, phorbol esters, and differentiation
signals. In addition, AP-1 behaves as a redox-sensitive transcription
factor in several cell types and is activated, to different
extents, under prooxidant conditions generated by treatment with agents
such as superoxide, H2O2,
UV light, -irradiation, and cytokines.117 118 119 120 121
In cell types of the vasculature, AP-1 is similarly activated
by prooxidant stimulus. In ECs, agents such as
H2O2,122
LDL,123 and oxLDL124 activate AP-1
DNA binding activity. In SMCs, oxLDL,125
H2O2,126 and
the lipid peroxidation product 4-hydroxy-2-nonenal127
have been shown to increase AP-1 expression or DNA binding activity.
Furthermore, regulation of the vascular inflammatory genes MCP-1 and
ICAM-1 by H2O2 is mediated
by AP-1 binding elements in the promoters of these
genes.128 129 Little information is known about the exact
mechanisms underlying ROS-mediated AP-1 activation; however, roles of
phospholipase A2, arachidonic
acid, LO, and protein kinase C have been proposed for
H2O2 induction of
c-fos130 and c-jun131 expression in VSMCs. In
addition, H2O2-induced AP-1
activation requires both tyrosine and serine/threonine
phosphorylation,132 and it has been
suggested that AP-1 activation under oxidative conditions may be, at
least in part, mediated by phosphorylation of Jun
proteins.133 Therefore, it appears that posttranslational
modifications after oxidative stress may modulate AP-1 activity.
The nuclear redox factor Ref-1 was initially cloned as a molecule that stimulated DNA binding of AP-1 via reduction of the conserved cysteine residues.134 Initially identified in HeLa nuclear extracts, Ref-1 has subsequently been shown to be ubiquitous and can stimulate DNA binding of other eukaryotic transcription factors in addition to AP-1.135 Thioredoxin (TRX) is another pleiotropic cellular factor that has thiol-mediated redox activity and functions to facilitate protein-nucleic acid interactions. TRX has also been shown to enhance the DNA binding activity of Jun and Fos via direct interaction with Ref-1.136 Therefore, the involvement of TRX and Ref-1 in redox modulation of AP-1 activity represents an example of a cellular redox cascade modulating transcription factor activity. Although not formally demonstrated in cell types of the vasculature, given the ubiquitous nature of Ref-1 and TRX, it is likely that this redox cascade may modulate AP-1 activity in the vasculature.
Paradoxically, in addition to oxidative stress, a number of
antioxidants, including dithiocarbamates, the antioxidant enzyme TRX,
and NAC have also been shown to stimulate the DNA binding and
transcriptional activity of AP-1 in several cell types.133
In monocytic cells, the upregulation of the ß2
integrin CD11c by PDTC was shown to involve a functionally important
AP-1 site and correlated with increased levels of AP-1 DNA binding by
PDTC.137 Similarly, PDTC-induced ICAM-1 expression
correlated with increased AP-1 binding to the PDTC-responsive region of
the ICAM-1 promoter in ECs.138 Paradoxically, antioxidants
have also been shown to block AP-1 transcriptional activity in ECs. The
antioxidant enzyme TRX peroxidase-1 blocked TNF-–induced AP-1
activation in ECs.139 Wung et al128
demonstrated that cyclic strain and
H2O2-induced MCP-1 gene
expression in ECs was mediated by an AP-1 element in the MCP-1
promoter. NAC and catalase prevented cyclic strain- or
H2O2-induced AP-1 binding
and MCP-1 expression. Thus, conflicting evidence exists over the role
of antioxidants in AP-1 activation. Unfortunately, little is known
regarding the precise mechanisms involved in redox-mediated AP-1 gene
expression. Because different antioxidants were used in these studies,
it is possible that the loci of action of different forms of
antioxidants may be specific to their chemical class. Likely, it is the
ultimate subtle balance of intracellular redox potential that will
determine the effect on AP-1 activity in response to either an
oxidative or an antioxidant challenge. Clearly, additional studies are
needed to clarify the role of AP-1 in antioxidant-mediated gene
expression.
Redox Regulation of NF-B
NF-B is an inducible transcription factor complex composed of
homodimeric or heterodimeric complexes of the Rel family of
transcriptional activators. The predominant form of NF-B
exists as a heterodimer of the p50 and p65 subunits. In unstimulated
cells, NF-B is held in an "inactive" form by sequestration in
the cytoplasm to the IB family of inhibitor proteins.
Agents that activate NF-B induce specific
phosphorylation events on IB via IB kinase
activity, which direct IB to a ubiquitination/proteosomal
degradation pathway. Degradation of IB thus unmasks the nuclear
localization sequence of NF-B and allows NF-B to enter the
nucleus and bind to specific DNA sequences in the regulatory regions of
its target genes.140
The NF-B transcription factor family controls the expression of a
multitude of genes involved in inflammation and proliferation. Recent
studies suggest the involvement of NF-B in a variety of acute and
chronic inflammatory diseases such as sepsis, Crohn disease, and
rheumatoid arthritis.140 In addition, it is becoming
increasingly apparent that NF-B is involved in the pathogenesis of
proliferative disorders of the vasculature, including
restenosis141 142 143 and
atherosclerosis.144 Studies have shown
that activated NF-B is present at increased levels in
the fibrotic thickened intima-media and atheromatous
areas of atherosclerotic lesions, whereas little or no
activated NF-B is detected in nondiseased
vessels.145 NF-B was also shown to be activated
by an atherogenic diet146 and by other cellular
products believed to be involved in atherogenesis, including
oxidized LDL54 147 148 and AGE.149 In
addition, several of the cytokines and growth factors found in
the atherosclerotic lesion, such as TNF- and IL-1ß,
activate NF-B in vitro in relevant cell types such as
macrophages, SMCs, ECs, and lymphocytes. Furthermore, many of
the genes that are regulated by NF-B encode for proteins such as
TNF-, IL-1, macrophage colony-stimulating factor (CSF),
granulocyte CSF, granulocyte-macrophage CSF, MCP-1, tissue
factor, VCAM-1, ICAM-1, and E-selectin, which function in regulating
critical processes in atherogenesis. Cumulatively, these observations
provide suggestive evidence for the role of NF-B in the pathogenesis
of atherosclerosis.
Given the widely held hypothesis implicating redox imbalances in the
pathogenesis of vascular disorders such as
atherosclerosis and restenosis, it is not
surprising that a substantial body of evidence indicates that
activation of NF-B in vascular cells may be controlled by the redox
status of the cell.150 In fact, NF-B was the first
eukaryotic transcription factor shown to respond directly
to oxidative stress. A common step in all of the activation mechanisms
that lead to IB degradation and NF-B nuclear translocation has
been suggested to involve ROS.151 152 153 154 This conclusion was
reached on the basis of the inhibition of NF-B activation by several
chemically distinct antioxidants, including NAC, dithiocarbamates,
vitamin E derivatives, GPx activators, and various metal
chelators. Many reports now exist demonstrating inhibition of NF-B
nuclear translocation by antioxidants, although the extent of this
block appears to vary with the cell type and the nature of the
signal.
Additional support for the involvement of ROS as a common
activator of NF-B is provided by many studies
demonstrating elevated levels of ROS by agents such as TNF-,
IL-1ß, phorbol 12-myristate 13-acetate, UV light, rays,
and lipid hydroperoxides. All of these agents are very potent
NF-B–activating agents, and antioxidants have been shown to block
both ROS production and resultant NF-B activation. Further
support for an essential role of ROS in NF-B activation derives from
experiments using exogenously added prooxidants. Initial pioneering
work by Schreck et al,151 152 153 among others, has shown
that in some cells lines,
H2O2 and
peroxide-containing molecules result in a rapid activation of NF-B.
However, incubation with superoxide, hydroxyl radicals, or
NO-generating compounds fail to cause activation, suggesting that like
the prokaryotic redox-regulated transcription factor OxyR, NF-B
activation is selectively mediated by peroxides. Conclusive support for
a role of H2O2 in NF-B
activation came from studies in a catalase-overexpressing cell line
that exhibited suppressed activation of NF-B in response to
TNF-.155 Addition of a catalase inhibitor
restored the NF-B response. Also, overexpression of cytosolic SOD,
which causes cytosolic H2O2
accumulation, potentiated the NF-B response. Likewise, stimulation
of GPx activity by selenium supplementation or GPx overexpression
decreased NF-B activation induced by
H2O2, IL-1ß, and
TNF-.156 157 These observations broaden the scope for
possible oxidants involved in NF-B activation from
H2O2 to a large variety of
hydroperoxides and to the products generated by multiple LOs and
cyclooxygenases, given that the classical GPx and
the phospholipid hydroperoxide GPx have been shown to decrease the
activity of cyclooxygenase,158
5-LO,159 and 15-LO.160 Cumulatively, these
observations have led to general agreement that NF-B activation is
at least facilitated by some oxidative reactions.
The target molecules that are subject to redox regulation during
NF-B activation remain unknown. It is unlikely that the NF-B
subunits themselves are directly activated by oxidation,
because only the reduced form of NF-B binds to DNA in
vitro,161 and attempts to activate isolated
NF-B by oxidation in vitro were unsuccessful.151 Direct
oxidative inactivation of IB is also not likely to be involved in
the redox regulation of NF-B, given that treatment of isolated
NF-B/IB complexes with
H2O2 in vitro failed to
dissociate IB or lead to NF-B DNA binding.151 162
Most evidence suggests that oxidative stresses induce, and antioxidants
prevent, the cytoplasmic-nuclear translocation of NF-B. Therefore,
the most likely scenario is that the signaling cascade leading to the
phosphorylation and subsequent degradation of IB is
regulated by redox processes. Indeed, it has recently been demonstrated
that antioxidants inhibit IB kinase activity and prevent the
phosphorylation and subsequent degradation of
IB.163 164
Although the primary mechanism of activation of NF-B by ROS appears
to be release from IB and its translocation to the nucleus, it is
possible that ROS may modulate the activity of NF-B by regulating
posttranslational modifications of the NF-B subunits themselves or
of other transcriptional cofactors that influence the transcriptional
activity of NF-B. Posttranslational modifications of NF-B
subunits may influence (1) DNA binding affinity and/or specificity, (2)
multimerization specificity with other NF-B subunits, or (3)
transcriptional activity. Although phosphorylation has
been shown to be important for some of these
events,165 166 167 no evidence exists to demonstrate a role
of ROS in these processes. Clearly, however, understanding the role of
redox processes in controlling the multitude of signaling events
regulating the activity of NF-B will provide important mechanistic
insights regarding redox modulation of transcriptional activity.
Peroxisome Proliferator-Activated Receptors
The PPARs are composed of members of the nuclear hormone receptor
superfamily of transcription factors, a large and diverse group of
proteins that mediate ligand-dependent transcriptional activation and
repression.168 PPARs are key players in lipid and glucose
metabolism and are implicated in metabolic
disorders predisposing to atherosclerosis, such as
dyslipidemia and diabetes. Recent reports suggest that
PPARs may play a role in inflammatory processes involved in the
pathogenesis of atherosclerosis and restenosis
by their ability to modulate monocytic gene
expression.169 170 171 Furthermore, PPAR expression and
functional activity have recently been observed in vascular cell types
such as EC172 and SMC.173 174 These studies
suggest that PPARs may be viewed as redox-sensitive transcription
factors in the vasculature by their ability to be selectively
activated by oxidatively modified fatty acids.
PPAR is one member of the PPAR family that has received considerable
attention because of its role in regulating, among other things, energy
balance and adipocyte differentiation. Identification of PPAR as the
receptor for the oral antidiabetic thiazolidinedione drugs linked this
receptor to glucose homeostasis.175 176 Two recent reports
suggest that PPAR is involved in the development of monocytes along
the macrophage lineage, in particular in the conversion of
monocytes to foam cells. Tontonoz et al177 demonstrated
that oxLDL, but not the parent LDL particle, induced the expression of
PPAR in foam cells of atherosclerotic lesions. In addition, exposure
of cells to PPAR agonists increased the binding of oxLDL, but not of
LDL. It was further shown that increased oxLDL binding was the result
of increased expression of the scavenger receptor CD36, but not 2 of
the other oxLDL receptors, scavenger receptor (SR)-A (SR-A) type
I or type II. In a companion paper,169 the nature of the
endogenous ligand for PPAR was examined, and it was
shown that oxLDL, but not native LDL, could serve as an
endogenous ligand for PPAR and could stimulate
PPAR-dependent transcription. This study identified the active
components of the oxLDL particle as 9- and 13-hydroxyoctadenoic acid by
demonstrating that these compounds themselves could mimic oxLDL with
respect to monocyte maturation, PPAR expression, PPAR-dependent
transcription, and induced CD36 expression. Together, these studies
point toward a direct role of oxLDL and components in the activation of
PPAR-dependent gene expression and regulation of the oxLDL receptor,
CD36. It remains to be determined whether activation by oxidized fatty
acids plays a significant role in PPAR-mediated processes in other
tissues. These observations suggest that activation of PPAR by oxLDL
in monocytes may contribute to foam cell conversion and thus potentiate
early events in the pathogenesis of
atherosclerosis.
In contrast to the proposed role of PPAR in potentially
proatherogenic events, it has recently been proposed that activation of
PPAR and PPAR may mediate anti-inflammatory responses in the
vessel wall (Figure 2). Two recent
reports demonstrated that specific agonists of PPAR suppress
proinflammatory gene expression in monocytes.170 171 In
addition, Staels et al173 demonstrate that inflammatory
responses in aortic SMCs (IL-1–induced production of IL-6,
prostaglandin, and COX-2) is blocked by specific
activators of the isoform of PPAR (PPAR), but not
PPAR. Furthermore, Poynter and Daynes178 demonstrated
that activation of PPAR in aged mice restored the cellular redox
balance to that of young animals. This was evidenced by a lowering of
tissue lipid peroxidation, elimination of constitutively active
NF-B, and a loss in spontaneous inflammatory cytokine
production after administration of PPAR
activators. These effects were not observed in animals
bearing a null mutation in PPAR. Also, administration of the
antioxidant, vitamin E, to aged mice (that contain reduced levels of
PPAR mRNA) resulted in an elevated expression of PPAR to levels
seen in younger mice. This observation suggests that balancing the
cellular redox state may provide a level of transcriptional regulation
for PPAR.
|
Taken together, these studies demonstrate that ligands for PPARs are
effective in reducing levels of inflammatory cytokines and
downstream markers of inflammation. It seems possible that suppression
of these proinflammatory signals by PPAR-mediated inhibition of
inflammatory gene expression may be one way to modulate or balance the
oxLDL-mediated proinflammatory events associated with
atherosclerosis. Thus, in a given cell, it is likely
that the subtle balance between proinflammatory signals and suppression
of these signals by transcriptional modulators (such as PPARs) will
determine the inflammatory status of the cell. Future work is needed to
clarify the role of oxLDL in PPAR-mediated signaling, especially in
vascular cell types. Cumulatively, these studies implicate a role for
oxidative processes (ie, oxidative modification of fatty acids) in
activation of PPAR and its potential involvement in disease
processes such as atherosclerosis and
restenosis. It will be interesting to determine what
role chemical antioxidants and therapeutic strategies aimed at
modifying PPAR function play in modulating PPAR-mediated molecular and
cellular events both in vitro and in vivo.
|
Conclusion |
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TopAbstractIntroductionEC Dysfunction and...Oxidative Signaling and Vascular...Atherogenic Risk Factors as...Redox-Sensitive Transcriptional...Redox Modulation of...ConclusionReferences |
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Alterations in the cellular redox status modify DNA binding and transactivation activities of a variety of transcriptional activators. This, in turn, leads to changes in expression of a variety of target genes with ultimate changes in cell function. Redox regulation of gene expression, therefore, appears to be a robust regulatory system that allows cells to adapt to environmental changes. In the vasculature, this is no exception. In considering the pathogenesis of atherosclerosis, a strong body of data supports the notion that ROS generated in response to environmental and physical risk factors modulate the signal transduction processes ultimately leading to vascular inflammatory gene expression. Vascular inflammatory genes, such as VCAM-1, E-selectin, and MCP-1, represent a subset of genes implicated in the pathogenesis of atherosclerosis, and the regulation of these genes is characterized by a linkage between redox-sensitive signals and the nuclear regulatory apparatus. Mechanistically this might suggest that the proposed therapeutic benefits of antioxidants in atherosclerosis might be caused by alterations in the molecular regulation of gene expression of endothelial, smooth muscle, and inflammatory cells. Therefore, redox-sensitive regulation of vascular gene expression represents an intriguing paradigm for understanding not only the pathogenesis of atherosclerosis but also for the development of novel therapeutic treatment strategies. Hopefully, elucidation of precise redox-regulated signaling pathways as they relate to the expression of atherogenic genes will encourage the exploration of novel treatment modalities targeting these redox-sensitive pathways. This hypothesis establishes an important framework to begin to understand how modulation of the redox-sensitive signaling process may be used to specifically alter the expression of genes involved in the pathogenesis of a variety of diseases.
|
Acknowledgments |
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We acknowledge Drs Margaret K. Offermann and Uday Saxena for critical review of the manuscript and Leola Hatcher for assistance with references.
Received January 18, 1999; accepted August 6, 1999.
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References |
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B. Rodriguez-Iturbe, N. D. Vaziri, J. Herrera-Acosta, and R. J. Johnson Oxidative stress, renal infiltration of immune cells, and salt-sensitive hypertension: all for one and one for all Am J Physiol Renal Physiol, April 1, 2004; 286(4): F606 - F616. [Abstract] [Full Text] [PDF]
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T. Ishii, K. Itoh, E. Ruiz, D. S. Leake, H. Unoki, M. Yamamoto, and G. E. Mann Role of Nrf2 in the Regulation of CD36 and Stress Protein Expression in Murine Macrophages: Activation by Oxidatively Modified LDL and 4-Hydroxynonenal Circ. Res., March 19, 2004; 94(5): 609 - 616. [Abstract] [Full Text] [PDF]
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C. Kunsch, J. Luchoomun, J. Y. Grey, L. K. Olliff, L. B. Saint, R. F. Arrendale, M. A. Wasserman, U. Saxena, and R. M. Medford Selective Inhibition of Endothelial and Monocyte Redox-Sensitive Genes by AGI-1067: A Novel Antioxidant and Anti-Inflammatory Agent J. Pharmacol. Exp. Ther., March 1, 2004; 308(3): 820 - 829. [Abstract] [Full Text] [PDF]
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J. J. Khatri, C. Johnson, R. Magid, S. M. Lessner, K. M. Laude, S. I. Dikalov, D. G. Harrison, H.-J. Sung, Y. Rong, and Z. S. Galis Vascular Oxidant Stress Enhances Progression and Angiogenesis of Experimental Atheroma Circulation, February 3, 2004; 109(4): 520 - 525. [Abstract] [Full Text] [PDF]
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M. A. Aller, J. L. Arias, M. P. Nava, and J. Arias Posttraumatic Inflammation Is a Complex Response Based on the Pathological Expression of the Nervous, Immune, and Endocrine Functional Systems Experimental Biology and Medicine, February 1, 2004; 229(2): 170 - 181. [Abstract] [Full Text] [PDF]
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M. Horiuchi, M. Tsutsui, H. Tasaki, T. Morishita, O. Suda, S. Nakata, S.-i. Nihei, M. Miyamoto, R. Kouzuma, M. Okazaki, et al. Upregulation of Vascular Extracellular Superoxide Dismutase in Patients With Acute Coronary Syndromes Arterioscler Thromb Vasc Biol, January 1, 2004; 24(1): 106 - 111. [Abstract] [Full Text] [PDF]
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P. Minuz, P. Patrignani, S. Gaino, F. Seta, M. L. Capone, S. Tacconelli, M. Degan, G. Faccini, A. Fornasiero, G. Talamini, et al. Determinants of Platelet Activation in Human Essential Hypertension Hypertension, January 1, 2004; 43(1): 64 - 70. [Abstract] [Full Text] [PDF]
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A. V. Chobanian, G. L. Bakris, H. R. Black, W. C. Cushman, L. A. Green, J. L. Izzo Jr, D. W. Jones, B. J. Materson, S. Oparil, J. T. Wright Jr, et al. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure Hypertension, December 1, 2003; 42(6): 1206 - 1252. [Abstract] [Full Text] [PDF]
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K. K. Griendling and G. A. FitzGerald Oxidative Stress and Cardiovascular Injury: Part I: Basic Mechanisms and In Vivo Monitoring of ROS Circulation, October 21, 2003; 108(16): 1912 - 1916. [Full Text] [PDF]
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D. B. Cowan, M. Jones, L. M. Garcia, S. Noria, P. J. del Nido, and F. X. McGowan Jr Hypoxia and Stretch Regulate Intercellular Communication in Vascular Smooth Muscle Cells Through Reactive Oxygen Species Formation Arterioscler Thromb Vasc Biol, October 1, 2003; 23(10): 1754 - 1760. [Abstract] [Full Text] [PDF]
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T. Aizawa, H. Wei, J. M. Miano, J.-i. Abe, B. C. Berk, and C. Yan Role of Phosphodiesterase 3 in NO/cGMP-Mediated Antiinflammatory Effects in Vascular Smooth Muscle Cells Circ. Res., September 5, 2003; 93(5): 406 - 413. [Abstract] [Full Text] [PDF]
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B. Lassegue and R. E. Clempus Vascular NAD(P)H oxidases: specific features, expression, and regulation Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2003; 285(2): R277 - R297. [Abstract] [Full Text] [PDF]
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C. L. Sundell, P. K. Somers, C. Q. Meng, L. K. Hoong, K.-L. Suen, R. R. Hill, L. K. Landers, A. Chapman, D. Butteiger, M. Jones, et al. AGI-1067: A Multifunctional Phenolic Antioxidant, Lipid Modulator, Anti-Inflammatory and Antiatherosclerotic Agent J. Pharmacol. Exp. Ther., June 1, 2003; 305(3): 1116 - 1123. [Abstract] [Full Text] [PDF]
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G. Basta, L. Venneri, G. Lazzerini, E. Pasanisi, M. Pianelli, N. Vesentini, S. Del Turco, C. Kusmic, and E. Picano In vitro modulation of intracellular oxidative stress of endothelial cells by diagnostic cardiac ultrasound Cardiovasc Res, April 1, 2003; 58(1): 156 - 161. [Abstract] [Full Text] [PDF]
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R. Dechend, C. Viedt, D. N. Muller, B. Ugele, R. P. Brandes, G. Wallukat, J.-K. Park, J. Janke, P. Barta, J. Theuer, et al. AT1 Receptor Agonistic Antibodies From Preeclamptic Patients Stimulate NADPH Oxidase Circulation, April 1, 2003; 107(12): 1632 - 1639. [Abstract] [Full Text] [PDF]
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W. Martinet, M. W.M. Knaapen, G. R.Y. De Meyer, A. G. Herman, and M. M. Kockx Overexpression of the Anti-Apoptotic Caspase-2 Short Isoform in Macrophage-Derived Foam Cells of Human Atherosclerotic Plaques Am. J. Pathol., March 1, 2003; 162(3): 731 - 736. [Abstract] [Full Text] [PDF]
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H. F. Lopes, K. L. Martin, K. Nashar, J. D. Morrow, T. L. Goodfriend, and B. M. Egan DASH Diet Lowers Blood Pressure and Lipid-Induced Oxidative Stress in Obesity Hypertension, March 1, 2003; 41(3): 422 - 430. [Abstract] [Full Text] [PDF]
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J.-C. Tardif, J. Gregoire, L. Schwartz, L. Title, L. Laramee, F. Reeves, J. Lesperance, M. G. Bourassa, P. L. L'Allier, M. Glass, et al. Effects of AGI-1067 and Probucol After Percutaneous Coronary Interventions Circulation, February 4, 2003; 107(4): 552 - 558. [Abstract] [Full Text] [PDF]
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M. Iglarz, R. M. Touyz, F. Amiri, M.-F. Lavoie, Q. N. Diep, and E. L. Schiffrin Effect of Peroxisome Proliferator-Activated Receptor-{alpha} and -{gamma} Activators on Vascular Remodeling in Endothelin-Dependent Hypertension Arterioscler Thromb Vasc Biol, January 1, 2003; 23(1): 45 - 51. [Abstract] [Full Text] [PDF]
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R. W. Alexander Oxidized LDL Autoantibodies, Endothelial Dysfunction, and Transplant-Associated Arteriosclerosis Arterioscler Thromb Vasc Biol, December 1, 2002; 22(12): 1950 - 1951. [Full Text] [PDF]
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T. K. Nakahashi, K. Hoshina, P. S. Tsao, E. Sho, M. Sho, J. K. Karwowski, C. Yeh, R.-B. Yang, J. N. Topper, and R. L. Dalman Flow Loading Induces Macrophage Antioxidative Gene Expression in Experimental Aneurysms Arterioscler Thromb Vasc Biol, December 1, 2002; 22(12): 2017 - 2022. [Abstract] [Full Text] [PDF]
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J. C. Fang, S. Kinlay, D. Behrendt, H. Hikita, J. L. Witztum, A. P. Selwyn, and P. Ganz Circulating Autoantibodies to Oxidized LDL Correlate With Impaired Coronary Endothelial Function After Cardiac Transplantation Arterioscler Thromb Vasc Biol, December 1, 2002; 22(12): 2044 - 2048. [Abstract] [Full Text] [PDF]
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J.-M. Li, N. P. Gall, D. J. Grieve, M. Chen, and A. M. Shah Activation of NADPH Oxidase During Progression of Cardiac Hypertrophy to Failure Hypertension, October 1, 2002; 40(4): 477 - 484. [Abstract] [Full Text] [PDF]
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W. Martinet, M. W.M. Knaapen, G. R.Y. De Meyer, A. G. Herman, and M. M. Kockx Elevated Levels of Oxidative DNA Damage and DNA Repair Enzymes in Human Atherosclerotic Plaques Circulation, August 20, 2002; 106(8): 927 - 932. [Abstract] [Full Text] [PDF]
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M. T Gewaltig and G. Kojda Vasoprotection by nitric oxide: mechanisms and therapeutic potential Cardiovasc Res, August 1, 2002; 55(2): 250 - 260. [Abstract] [Full Text] [PDF]
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G. NICKENIG, S. BAUDLER, C. MULLER, C. WERNER, N. WERNER, H. WELZEL, K. STREHLOW, and M. BOHM Redox-sensitive vascular smooth muscle cell proliferation is mediated by GKLF and Id3 in vitro and in vivo FASEB J, July 1, 2002; 16(9): 1077 - 1086. [Abstract] [Full Text] [PDF]
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H. Fan, B. Sun, Q. Gu, A. Lafond-Walker, S. Cao, and L. C. Becker Oxygen radicals trigger activation of NF-kappa B and AP-1 and upregulation of ICAM-1 in reperfused canine heart Am J Physiol Heart Circ Physiol, May 1, 2002; 282(5): H1778 - H1786. [Abstract] [Full Text] [PDF]
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C. Kumaran and K. Shivakumar Calcium- and superoxide anion-mediated mitogenic action of substance P on cardiac fibroblasts Am J Physiol Heart Circ Physiol, May 1, 2002; 282(5): H1855 - H1862. [Abstract] [Full Text] [PDF]
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T. Ide, H. Tsutsui, N. Ohashi, S. Hayashidani, N. Suematsu, M. Tsuchihashi, H. Tamai, and A. Takeshita Greater Oxidative Stress in Healthy Young Men Compared With Premenopausal Women Arterioscler Thromb Vasc Biol, March 1, 2002; 22(3): 438 - 442. [Abstract] [Full Text] [PDF]
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M. Rodriguez-Porcel, L. O Lerman, D. R Holmes Jr., D. Richardson, C. Napoli, and A. Lerman Chronic antioxidant supplementation attenuates nuclear factor-{kappa}B activation and preserves endothelial function in hypercholesterolemic pigs Cardiovasc Res, March 1, 2002; 53(4): 1010 - 1018. [Abstract] [Full Text] [PDF]
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J.-M. Li, A. M. Mullen, S. Yun, F. Wientjes, G. Y. Brouns, A. J. Thrasher, and A. M. Shah Essential Role of the NADPH Oxidase Subunit p47phox in Endothelial Cell Superoxide Production in Response to Phorbol Ester and Tumor Necrosis Factor-{alpha} Circ. Res., February 8, 2002; 90(2): 143 - 150. [Abstract] [Full Text] [PDF]
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