© 2000 American Heart Association, Inc.
Brief Review |
Modulation of Protein Kinase Activity and Gene Expression by Reactive Oxygen Species and Their Role in Vascular Physiology and Pathophysiology
From the Division of Cardiology, Emory University, Atlanta, Ga.
Correspondence to Kathy K. Griendling, PhD, Division of Cardiology, Emory University School of Medicine, 1639 Pierce Dr, 319 WMB, Atlanta, GA 30322. E-mail kgriend{at}emory.edu
 |
Abstract |
|---|
 Top Abstract IntroductionProduction and Metabolism of...Regulation of Gene Expression...Role of ROS in...Conclusions and Future...References |
|---|
Abstract—Emerging evidence indicates that reactive oxygen species, especially superoxide and hydrogen peroxide, are important signaling molecules in cardiovascular cells. Their production is regulated by hormone-sensitive enzymes such as the vascular NAD(P)H oxidases, and their metabolism is coordinated by antioxidant enzymes such as superoxide dismutase, catalase, and glutathione peroxidase. Both of these reactive oxygen species serve as second messengers to activate multiple intracellular proteins and enzymes, including the epidermal growth factor receptor, c-Src, p38 mitogen-activated protein kinase, Ras, and Akt/protein kinase B. Activation of these signaling cascades and redox-sensitive transcription factors leads to induction of many genes with important functional roles in the physiology and pathophysiology of vascular cells. Thus, reactive oxygen species participate in vascular smooth muscle cell growth and migration; modulation of endothelial function, including endothelium-dependent relaxation and expression of a proinflammatory phenotype; and modification of the extracellular matrix. All of these events play important roles in vascular diseases such as hypertension and atherosclerosis, suggesting that the sources of reactive oxygen species and the signaling pathways that they modify may represent important therapeutic targets.
Key Words: reactive oxygen species • vascular smooth muscle • endothelial cells • hypertension • atherosclerosis
|
Introduction |
|---|
|
TopAbstractIntroductionProduction and Metabolism of...Regulation of Gene Expression...Role of ROS in...Conclusions and Future...References |
|---|
Reactive oxygen species (ROS) are some of the newest additions to the family of second-messenger molecules. Although one ROS, nitric oxide (NO·), has been known for years to serve as a signaling molecule by activating guanylate cyclase, it has only recently become apparent that other ROS, including superoxide (O2-·) and hydrogen peroxide (H2O2), can alter the function of specific proteins and enzymes as well. In most cases, the mechanism by which these agents interact with their molecular targets is still unknown, but it is clear that they can mediate agonist-stimulated signaling. In this review, we will discuss redox-sensitive signaling cascades in vascular cells; their alteration by agonists, with particular attention to angiotensin II (Ang II); and their relevance to cardiovascular disease.
|
Production and Metabolism of ROS |
|---|
|
TopAbstractIntroductionProduction and Metabolism of...Regulation of Gene Expression...Role of ROS in...Conclusions and Future...References |
|---|
Virtually all types of vascular cells produce O2-· and H2O2.1 In addition to mitochondrial sources of ROS, O2-· and/or H2O2 can be derived from xanthine oxidase, cyclooxygenase, lipoxygenase, NO synthase, heme oxygenases, peroxidases, hemoproteins such as heme and hematin, and NAD(P)H oxidases. Several investigators have shown that these latter enzymes, the membrane-associated NAD(P)H oxidase(s), are the primary physiological producers of ROS in vascular tissue.2 3 4 Of importance, the activity of these enzymes can be modulated by vasoactive hormones and the low-molecular-weight G protein rac-1,4 5 6 7 providing a critical characteristic of any second messenger: regulation of its production. Metabolism of these ROS is also tightly controlled. Dismutation of O2-· by superoxide dismutase (SOD) produces the more stable ROS H2O2, which in turn is converted to water by catalase and glutathione peroxidase. Expression of antioxidant enzymes can be altered by hormones such as Ang II, tumor necrosis factor (TNF)-
, and interleukin (IL)-1ß, thus profoundly
affecting ROS levels.8 9 10 11 The tight regulation of both
production and removal of ROS makes fluctuations in their
levels transient, another requirement for second messengers. ROS may
also act as an intracellular "rheostat," closely modulating the
activity of a discrete set of biochemical reactions. A schematic of the
balance between oxidative and reductive states of the cell and the
hormones, enzymes, and compounds that can alter this balance and thus,
the overall response of the cell, is presented in Figure 1
.
|
Vascular NAD(P)H Oxidases
The major sources of ROS in the vessel wall, the vascular NAD(P)H
oxidases, are similar in structure to the neutrophil NADPH oxidase,
which consists of 4 major subunits: a cytochrome b558,
comprising gp91phox and p22phox, and 2 cytosolic components, p47phox
and p67phox. A member of the low-molecular-weight G protein rac family
participates in the assembly of the active complex. Table 1 summarizes the expression of the major
phox subunits in vascular cells. Although the expression pattern of
these molecules has been demonstrated, with the exception of p22phox in
vascular smooth muscle cells (VSMCs)12 and
endothelial cells13 and rac15
and p67phox in fibroblasts,14 it remains to be determined
which subunits participate in functional complexes in specific cell
types and/or whether as-yet-unidentified proteins take part in
O2-· formation. If
cardiovascular cells contain a neutrophil-like oxidase,
it is essential to identify the electron transport moiety of the
protein. Although gp91phox may serve this function in
endothelial and adventitial cells, its apparent absence
in SMCs suggests that a substitute must exist. Recently, several
homologues of gp91phox have been cloned, and one of them, termed mox-1,
for mitogenic oxidase (now known as nox-1, for
NADPH oxidase), has been shown to be expressed in
VSMCs.15 In these cells, nox-1 mediates the
proliferative response to serum, and nox-1 antisense attenuates
O2-· production in
response to platelet-derived growth factor (PDGF).15
Two other nox proteins have also been found: a 138-kDa protein (tox-1)
that is the main, if not the sole, component of the thyroid
oxidase,16 and a 578–amino acid protein,
renox, that is expressed mainly in the kidney.17
Expression of these oxidases in vascular cells and their interaction
with other phox subunits remain to be determined.
|
Regulation of ROS Production by Vasoactive Agonists and
Mechanical Forces
There is good evidence for agonist-induced ROS production
in both SMCs and endothelial cells. One of the first
reports that the vascular NAD(P)H oxidase was hormone sensitive showed
that Ang II treatment of SMCs increases intracellular
O2-·
production.4 Ang II–stimulated
O2-· is converted to
H2O2 as early as 1 minute
after addition of hormone.18 Superoxide production
in response to Ang II occurs when either NADH or NADPH is used as a
substrate and is inhibitable by diphenylene iodonium (DPI), a compound
that binds to and inhibits flavin-containing oxidases; Tiron, an
O2-· scavenger;
N-acetylcysteine (NAC), which increases intracellular
glutathione pools; and SOD.4 Treatment with antisense
p22phox to depress NAD(P)H oxidase expression also blocks Ang
II–induced O2-·
production.12 Activation of this oxidase by
Ang II appears to involve arachidonic acid
metabolites,19 perhaps derived ultimately from
phospholipase D–mediated phosphatidylcholine
hydrolysis.20 Ang II also stimulates NAD(P)H-dependent
O2-· production in
endothelial cells21 22 23 and adventitial
fibroblasts.14
Other agonists and mechanical forces have also been shown to increase
ROS production in vascular cells. PDGF, thrombin, TNF-, and
lactosylceramide activate NAD(P)H oxidase–dependent
O2-· production in
SMCs.6 7 24 25 26 Fibroblasts exhibit increased NADH- or
NADPH-driven O2-·
production in response to TNF-, IL-1, and
platelet-activating factor.27 28 In
endothelial cells, mechanical forces, including cyclic
stretch and laminar and oscillatory shear stress, stimulate NAD(P)H
oxidase activity.29 30 The upstream signals responsible
for oxidase activation in each of these cell types with each of these
stimuli remain to be established.
Signal Transduction Pathways Modulated by ROS
In order for ROS to modify the response of a cell to an agonist,
it must affect specific signaling cascades. Over the past several
years, many redox-sensitive proteins have been identified, and in some
cases, it has been shown that hormonal activation is mediated by ROS.
Often, both redox-sensitive and redox-insensitive pathways contribute
to activation of a particular enzyme (Figure 2). The relationship between signaling
cascades known to respond to ROS is depicted in Figure 2, and each pathway is discussed individually below.
|
Proximal Tyrosine Kinases
Growing evidence indicates that the epidermal growth factor
receptor (EGF-R) and the PDGF receptor (PDGF-R) serve not only as
receptors for EGF and PDGF, respectively, but also as a scaffold for
assembly of signaling complexes by G protein–coupled receptors such as
those for Ang II.31 32 It is of interest that
transactivation of both of these growth factor receptors is redox
sensitive. In SMCs, H2O2
induces tyrosine phosphorylation of the EGF-R and
stimulates its association with Shc (src homology complex)–Grb2
(growth factor receptor–bound protein 2)–Sos (son-of-sevenless)
complex to activate subsequent signaling cascades (Figure 2
).33 Furthermore, Ang II–induced EGF-R
transactivation is mediated through NAD(P)H oxidase–derived ROS
because it is strongly inhibited by several antioxidants in SMCs and by
NAC in cardiac fibroblasts.34 35 Heeneman et
al36 have most recently reported that Ang II–induced
phosphorylation of the Shc/PDGFß-R complex is
mediated by ROS.
Although phosphorylation of the EGF-R by Ang II
is redox sensitive, phosphorylation by EGF is not,
suggesting that an even more proximal kinase than the EGF-R exists.
Recently, we have shown that this kinase is c-Src.34 c-Src
is an important signaling molecule with many functions: it
phosphorylates phospholipase C-
37 ; forms
complexes with the EGF-R,32 paxillin,38
and Janus kinase (JAK)-239 ; and mediates activation
of mitogen-activated protein kinases (MAPKs).40 In
mouse fibroblasts, H2O2
directly activates c-Src.40 Moreover, Ang
II–induced c-Src phosphorylation at both the
autophosphorylation site (Y418) and the
SH2-domain (Y215) is inhibited by antioxidants,
suggesting that in VSMCs,
H2O2 is a proximal mediator
of agonist-induced c-Src activation.34
Another signaling molecule that is activated quite early after
receptor stimulation is the low-molecular-weight GTP-binding protein
Ras. Ras has a dual role in redox-sensitive signaling: it mediates
activation of the NADH/NADPH oxidase to generate intracellular
ROS,5 and it is also activated by ROS in vivo and
in vitro.41 42 43 ROS activate Ras via an oxidative
modification of cysteine-118, leading to inhibition of the GDP-GTP
exchange.42 Moreover, ROS-triggered Ras activation induces
recruitment of phosphatidylinositol 3'-kinase to Ras, an event that is
required for activation of downstream signals such as Akt and MAPK
(Figure 2 and below).44
Mitogen-Activated Protein Kinases
The MAPKs are a family of serine/threonine kinases that control
cellular responses to growth, apoptosis, and stress signals.
There are 4 main MAPKs, including extracellular signal–regulated
kinases (ERK1/2), c-Jun N-terminal kinases (JNKs, also
termed SAPKs), p38 MAPKs, and big MAPK-1. These proteins are the best
studied in terms of their redox sensitivity. In SMCs,
H2O2 has been shown to
activate p38 MAPK,45 46 JNK,46
and big MAPK-1.47 Its effects on ERK1/2 are controversial,
with some reports showing inhibition and others demonstrating
stimulation.45 46 48 49 In terms of agonist-induced
activation of these enzymes, it has been clearly demonstrated that p38
MAPK and JNK activation by Ang II is inhibited by antioxidants (DPI,
NAC), p22phox antisense, or overexpression of
catalase.45 50 Recently, it has been shown that
arachidonic acid stimulates JNK via Rac-1–dependent
H2O2
production.51 Because arachidonic
acid is produced in response to many vasoactive hormones, this may
represent a common mechanism of activation. Moreover, although
PDGF-induced ERK1/2 phosphorylation is inhibited by
incubation with catalase,25 Ang II activation of these
enzymes is not.45 49 50
In endothelial cells, H2O2 activates p38 MAPK and its downstream target, MAPK-activated protein (MAPKAP) kinase 2/3, leading to phosphorylation of heat-shock protein 27 (Hsp27).52 53 ERK1/2 activation also seems to be redox sensitive in this cell type, based on the observation that shear stress–induced ERK1/2 phosphorylation is inhibited by antioxidants and dominant-negative Rac-1.54 In neonatal rat ventricular myocytes, all 3 MAPKs (ERK1/2, p38 MAPK, and JNK) have been demonstrated to be activated by H2O2.55 Thus, regulation of MAPK activity by ROS varies not only among family members but also among cells.
Akt
The recently identified serine/threonine kinase Akt/protein kinase
B has been shown to play a key role in many cellular processes,
including cell survival and protein synthesis.56 Akt
inhibits glycogen synthase kinase 3 and activates p70S6K and
the transcription factors activator protein (AP)-1 and
E2F.56 Similar to p38 MAPK, both exogenous
H2O2 and Ang II
activate Akt in SMCs.57 Ang II–induced Akt
phosphorylation is inhibited by DPI or overexpression
of catalase, suggesting a role for NAD(P)H oxidase–derived ROS in
agonist-induced Akt activation.
H2O2 stimulation of Akt has
also been reported in other nonvascular cell types, including NIH3T3
fibroblasts, human embryonic kidney 293 cells, and HeLa and Jurkat
cells.58 59 60 It is noteworthy that Konishi et
al59 demonstrated that
H2O2-induced Akt activation
caused association with Hsp27, which itself is also
phosphorylated by
H2O2.52 61
Furthermore, MAPKAP kinase-2, a substrate of p38
MAPK,62 63 can phosphorylate Akt in
vitro,64 65 raising the possibility that
H2O2 may
phosphorylate both Akt and Hsp27 by activation of p38
MAPK.
Other Candidate Redox-Sensitive Enzymes
Most likely, we have only scratched the surface of the cadre of
oxidant-sensitive signaling pathways. Many proteins, including
phospholipase D, Fyn, proline-rich tyrosine kinase (Pyk) 2, JAK2, and
signal transducer and activator of transcription (STAT) 1,
appear to be redox sensitive, based on their activation by addition of
exogenous ROS. For example,
H2O2 and lipid
hydroperoxides activate phospholipase D in
endothelial cells.66 In mouse fibroblasts,
H2O2 activates JAK2
via Fyn kinase, resulting in the stimulation of Ras
activity.67 Pyk2 has also been reported to be redox
sensitive, because H2O2 and
the strong oxidant diamide both increase Pyk2
phosphorylation.68 Furthermore,
PDGF-induced STAT activation is inhibited by antioxidants such as NAC
and DPI.69 Although, for the most part, the role of ROS in
activation of these pathways by agonists has not been studied, their
clear relationship with ROS suggests that they are potentially among
the proteins that mediate redox-sensitive
physiological responses.
|
Regulation of Gene Expression by ROS |
|---|
|
TopAbstractIntroductionProduction and Metabolism of...Regulation of Gene Expression...Role of ROS in...Conclusions and Future...References |
|---|
Because multiple hormones and growth factors alter tissue and intracellular levels of ROS and various critical signaling pathways are activated by ROS, it is not surprising that many cardiovascular-related genes are redox sensitive. Perusal of Table 2
indicates that ROS
regulate several general classes of genes, including adhesion molecules
and chemotactic factors, antioxidant enzymes, and vasoactive
substances. Some of these are clearly an adaptive response, such as the
induction of SOD and catalase by
H2O2.70 Most
redox-sensitive genes have been identified because they are responsive
to externally applied oxidant stress; only a few have been demonstrated
to be downstream of an endogenous source of ROS, such as
the NAD(P)H oxidase. These include TNF- and lactosylceramide
induction of intercellular adhesion molecule (ICAM-1)26 71
and Ang II, PDGF, and TNF- stimulation of monocyte chemotactic
protein (MCP)-1.24 72 In contrast, stimulation of MCP-1 by
IL-1ß24 in VSMCs is not affected by antioxidants,
suggesting that the control of gene expression by ROS is both stimulus
and tissue specific.
|
Induction of several genes by cytokines is inhibited by NO donors, including vascular cell adhesion molecule (VCAM)-1,73 74 ICAM-1,73 and monocyte colony-stimulating factor (M-CSF).75 This is an interesting mechanism of regulation because NO· appears to act in a cGMP-independent manner to inhibit expression at the level of transcription.76 Not only can NO· alter the activity and expression of transcription factors, but also it scavenges O2-· to form peroxynitrite, thus modulating O2-·-dependent transcription as well.
Regulation of gene expression by oxidant stress occurs at various
levels. In some cases, regulation of the gene is redox sensitive owing
to the susceptibility of upstream signaling pathways to ROS. For
example, induction of early growth response (Egr)-1 by cyclic strain
has been shown to depend on redox-sensitive activation of the
Ras-Raf-ERK1/2 pathway.77 Moreover,
H2O2-induced AP-1 binding
in porcine aortic endothelial cells requires activation
of Src.78 In other cases, ROS mediate increased turnover,
expression, or translocation of specific transcription factors, thus
modifying their activity. This mechanism has been shown to be effective
for both the nuclear factor (NF)-
B and AP-1 transcription factors.
Hydroperoxy fatty acids and
H2O2 increase the
expression of Fos and Jun, 2 proteins that form heterodimers and
activate AP-1.79 NO· increases the transcription
of IB, the inhibitory factor that binds NF-B and
causes retention of this transcription factor in a cytoplasmic,
inactive form.73 The turnover of IB protein is also
oxidant sensitive: antioxidants can prevent agonist-stimulated IB
phosphorylation and degradation.73
Conversely, H2O2 increases
nuclear translocation of NF-B, contributing to the induction of
genes responsive to this transcription factor.78
An additional level of redox regulation of gene expression is that the
affinity of certain transcription factors for their cognate DNA-binding
sites can be directly modified by ROS. This mechanism was first
identified in bacteria, where excess
H2O2 interacts with the
oxyR regulon, and O2-· or
NO· activates the SoxRS regulon to control the expression of
a subset of genes, including MnSOD and aconitase.80 The
oxyR-binding motif has also been shown to function as a redox-sensitive
transcriptional enhancer in mammalian cells.81 Since then,
several mammalian transcription factors have been shown to be directly
modified by ROS or by reducing proteins that modify cysteine residues
involved in DNA binding. Transcription factors in this category include
AP-1, NF-B, and most likely hypoxia-inducible factor
(HIF)-1.82 83 Both Fos and Jun have a conserved cysteine
in a basic motif that, when oxidized, interferes with the binding of
these proteins to AP-1 consensus sequences. Conversely, if Fos/Jun
heterodimers are bound to AP-1, they cannot be oxidized.82
The oxidation state of these important proteins is controlled by redox
factor (REF)-1, a protein that, in cooperation with thioredoxin,
promotes the cycling of the critical cysteines between reduced and
oxidized forms.82 84 Thioredoxin also regulates
HIF-1–dependent transcription83 and modifies the DNA
binding and transcriptional activity of NF-B by reducing cysteine
62.85 These studies clearly indicate the importance of the
nuclear redox state in regulating gene expression.
|
Role of ROS in Vascular Physiology and Pathophysiology |
|---|
|
TopAbstractIntroductionProduction and Metabolism of...Regulation of Gene Expression...Role of ROS in...Conclusions and Future...References |
|---|
The intracellular and extracellular production of ROS and the consequent activation of specific signaling pathways and induction of redox-sensitive genes coordinate several integrated physiological responses in cardiovascular tissue, including growth of smooth muscle, induction of an inflammatory response, impairment of endothelium-dependent relaxation, and cardiac hypertrophy. Each of these responses, when uncontrolled, contributes to vascular disease.
Vascular Smooth Muscle Growth, Hypertrophy, and
Apoptosis
A characteristic of hypertension is hypertrophy of
large vessels.86 We have demonstrated that Ang II–induced
hypertrophy of SMCs is dependent on intracellularly
produced H2O2, which is
derived, at least in part, from an NAD(P)H oxidase.4 12 18
Ang II–induced hypertrophy can be inhibited by
DPI,4 attenuation of NAD(P)H oxidase activity by
transfection of antisense p22phox,12 and catalase
overexpression.18 Similar findings were reported for
cardiac myocytes, in which Ang II–induced hypertrophy was
associated with intracellular production of ROS and was blocked
by antioxidants.87
Other vascular disorders such as restenosis have a significant proliferative component, resulting from SMC and/or fibroblast migration and multiplication in the neointima.88 Sundaresan et al25 demonstrated a clear requirement for H2O2 in PDGF-induced proliferation. Migration in response to this agonist is also inhibited by catalase, suggesting that it, too, is mediated by ROS. Similar results were found by Brown et al,89 who showed that overexpression of catalase in SMCs not only inhibited serum-induced [3H]thymidine incorporation and proliferation but also promoted apoptosis. Phenylephrine-induced proliferation of rabbit aortic SMCs has also been shown to require H2O2.90 Proof that balloon angioplasty increases oxidant stress has been provided in 2 studies. Within 30 minutes after injury, glutathione levels fall by 63%, coincident with medial smooth muscle apoptosis, suggesting that this early step in the response to injury is associated with severe oxidant stress. Importantly, administration of NAC or pyrrolidine dithiocarbamate prevents the glutathione loss and the smooth muscle apoptosis.91 In another study, Nunes et al92 showed that vascular O2-· was increased 2.5-fold in injured arteries compared with uninjured controls. Moreover, treatment with either probucol or the combination of vitamins C and E normalized O2-· levels and partially suppressed neointimal formation.93 Davies et al94 have recently reported that p38 MAPK is upregulated after injury, suggesting that this signaling pathway might also be a redox-sensitive target in vivo.
Endothelial Dysfunction
Endothelial dysfunction is a hallmark of multiple
vascular diseases, including hypertension,
atherosclerosis, and diabetes mellitus. Impaired
endothelial function has several consequences, the most
important of which is decreased endothelium-dependent
vasodilation. The endothelial cell redox rheostat is
primarily regulated by the dynamic production of and
interaction between NO· and
O2-·. NO· is the most
potent endogenous vasodilator and inhibits smooth muscle
proliferation and migration, adhesion of leukocytes to the
endothelium, and platelet
aggregation.95 In cholesterol-fed rabbits,
O2-· is increased in the
aorta,96 and treatment with polyethylene glycol–SOD
reverses the impairment in endothelium-dependent
relaxation.97 In the same animal model, treatment with
probucol (a lipid-lowering agent with potent antioxidant properties)
corrects endothelial dysfunction and lowers
O2-·.98 Impaired
endothelium-dependent vasodilation also occurs in
hypertension, such as that produced by infusion of rats with Ang
II,3 restriction of blood flow to 1 kidney,99
and administration of deoxycorticosterone acetate-salt.100
The endothelial dysfunction that accompanies Ang II
infusion or deoxycorticosterone acetate-salt can be corrected by
administration of liposomal or matrix-targeted
SOD,100 101 102 providing further proof that ROS, and
specifically O2-·, are
involved in this response.
The Inflammatory Response
Another consequence of endothelial dysfunction and
SMC activation is increased monocyte adhesion, foam cell formation, and
thrombosis. As noted above, pro-oxidant agonists such as Ang II and
TNF- induce the expression of proinflammatory molecules such as
VCAM-1, MCP-1, and the thrombin receptor.6 72 103 104 105 106
Each of these molecules is in turn redox
sensitive,72 104 107 and in the case of MCP-1 and the
thrombin receptor, a role for ROS in Ang II–mediated gene expression
has been demonstrated.72 104
Matrix Remodeling
Collagen degradation depends on the activity of enzymes known as
metalloproteinases (MMPs). MMP-2 (gelatinase A, which degrades collagen
IV from the basal membrane) and MMP-9 (gelatinase B, which acts on
collagen I fibers) are secreted by macrophages and vascular
myocytes in an inactive form.108 MMP-9 expression is
increased in the shoulder region of atherosclerotic plaques; ie, in the
sites prone to plaque rupture.109 Rajagopalan et
al110 demonstrated that pro–MMP-9 and pro–MMP2 secreted
into the medium of cultured human SMCs are activated by ROS.
Moreover, NAC treatment prevents MMP-9 expression and activation in
hypercholesterolemic rabbits,111
suggesting a mechanism for how antioxidants may contribute to plaque
stabilization.
|
Conclusions and Future Directions |
|---|
|
TopAbstractIntroductionProduction and Metabolism of...Regulation of Gene Expression...Role of ROS in...Conclusions and Future...References |
|---|
Much remains to be learned concerning the signaling pathways and genes that are regulated by ROS. Because redox-sensitive responses appear at times to be cell specific, it will be important to identify the sources of oxidant stress in each cell, the mechanism of regulation of antioxidant enzymes, and the effect of ROS on signaling pathways specific to the function of that particular cell and to gain further insight into the physiological responses affected by oxidant stress. An understanding of these events will enable us to devise therapeutic strategies to target specific cellular events contributing to vascular disease.
|
Acknowledgments |
|---|
This review was supported by NIH grants HL38206, HL58000, and HL58863. The authors thank Carolyn Morris for excellent secretarial assistance.
Received May 26, 2000; accepted August 10, 2000.
|
References |
|---|
|
TopAbstractIntroductionProduction and Metabolism of...Regulation of Gene Expression...Role of ROS in...Conclusions and Future...References |
|---|
1. Griendling KK, Sorescu D, Ushio-Fukai M. NAD(P)H oxidase: role in cardiovascular biology and disease. Circ Res. 2000;86:494–501.
2.
Mohazzab KM, Kaminski PM, Wolin MS. NADH
oxidoreductase is a major source of superoxide anion in bovine
coronary artery endothelium. Am J
Physiol. 1994;266:H2568–H2572.
3. Rajagopalan S, Kurz S, Münzel T, Tarpey M, Freeman BA, Griendling KK, Harrison DG. Angiotensin II mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation: contribution to alterations of vasomotor tone. J Clin Invest. 1996;97:1916–1923.[Medline] [Order article via Infotrieve]
4.
Griendling KK, Minieri CA, Ollerenshaw JD,
Alexander RW. Angiotensin II stimulates NADH and NADPH
oxidase activity in cultured vascular smooth muscle cells. Circ
Res. 1994;74:1141–1148.
5.
Irani K, Xia Y, Zweier JL, Sollott SJ, Der CJ,
Fearon ER, Sundaresan M, Finkel T, Goldschmidt-Clermont PJ.
Mitogenic signaling mediated by oxidants in ras-transformed
fibroblasts. Science. 1997;275:1649–1652.
6.
De Keulenaer GW, Alexander RW, Ushio-Fukai M,
Ishizaka N, Griendling KK. Tumor necrosis factor-
activates a p22phox-based NADH oxidase in vascular smooth
muscle cells. Biochem J. 1998;329:653–657.
7.
Patterson C, Ruef J, Madamanchi NR, Barry-Lane
P, Hu Z, Horaist C, Ballinger CA, Brasier AR, Bode C, Runge MS.
Stimulation of a vascular smooth muscle cell NAD(P)H oxidase by
thrombin: evidence that p47(phox) may participate in forming this
oxidase in vitro and in vivo. J Biol Chem. 1999;274:19814–19822.
8.
Fukai T, Siegfried MR, Ushio-Fukai M,
Griendling KK, Harrison DG. Modulation of extracellular superoxide
dismutase expression by angiotensin II and hypertension.
Circ Res. 1999;85:23–28.
9.
Shaffer JB, Treanor CP, Del Vecchio PJ.
Expression of bovine and mouse endothelial cell
antioxidant enzymes following TNF- exposure. Free Radic
Biol Med. 1990;8:497–502.[Medline]
[Order article via Infotrieve]
10. Visner GA, Chesrown SE, Monnier J, Ryan US, Nick HS. Regulation of manganese superoxide dismutase: IL-1 and TNF induction in pulmonary artery and microvascular endothelial cells. Biochem Biophys Res Commun. 1992;188:453–462.[Medline] [Order article via Infotrieve]
11. Crosby AJ, Wahle KW, Duthie GG. Modulation of glutathione peroxidase activity in human vascular endothelial cells by fatty acids and the cytokine interleukin-1ß. Biochim Biophys Acta. 1996;1303:187–192.[Medline] [Order article via Infotrieve]
12.
Ushio-Fukai M, Zafari AM, Fukui T, Ishizaka N,
Griendling KK. p22phox is a critical component of the
superoxide-generating NADH/NADPH oxidase system and regulates
angiotensin II-induced hypertrophy in vascular
smooth muscle cells. J Biol Chem. 1996;271:23317–23321.
13.
Gorlach A, Brandes RP, Nguyen K, Amidi M,
Dehghani F, Busse R. A gp91phox containing NADPH oxidase selectively
expressed in endothelial cells is a major source of
oxygen radical generation in the arterial wall. Circ
Res. 2000;87:26–32.
14.
Pagano PJ, Chanock SJ, Siwik DA, Colucci WS,
Clark JK. Angiotensin II induces p67phox mRNA expression
and NADPH oxidase superoxide generation in rabbit aortic adventitial
fibroblasts. Hypertension. 1998;32:331–337.
15. Suh Y, Arnold RS, Lassègue B, Shi J, Xu X, Sorescu D, Chung AB, Griendling KK, Lambeth JD. Cell transformation by the superoxide-generating oxidase mox1. Nature. 1999;401:79–82.[Medline] [Order article via Infotrieve]
16.
Dupuy C, Ohayon R, Valent A, Noel-Hudson MS,
Deme D, Virion A. Purification of a novel flavoprotein involved in the
thyroid NADPH oxidase: cloning of the porcine and human cDNAs.
J Biol Chem. 1999;274:37265–37269.
17.
Geiszt M, Kopp JB, Varnai P, Leto TL.
Identification of Renox, an NAD(P)H oxidase in kidney. Proc Natl
Acad Sci U S A. 2000;97:8010–8014.
18.
Zafari AM, Ushio-Fukai M, Akers M, Yin Q, Shah
A, Harrison DG, Taylor WR, Griendling KK. Novel role of NADH/NADPH
oxidase-derived hydrogen peroxide in angiotensin
II–induced hypertrophy of rat vascular smooth muscle
cells. Hypertension. 1998;32:488–495.
19. Zafari AM, Ushio-Fukai M, Minieri CA, Akers M, Lassègue B, Griendling KK. Arachidonic acid metabolites mediate angiotensin II-induced NADH/NADPH oxidase activity and hypertrophy in vascular smooth muscle cells. Antioxidants Redox Signaling. 1999;1:167–179.[Medline] [Order article via Infotrieve]
20.
Touyz RM, Schiffrin EL. Ang II–stimulated
superoxide production is mediated via phospholipase D in human
vascular smooth muscle cells. Hypertension. 1999;34:976–982.
21. Munzel T, Hink U, Heitzer T, Meinertz T. Role for NADPH/NADH oxidase in the modulation of vascular tone. Ann N Y Acad Sci. 1999;874:386–400.[Medline] [Order article via Infotrieve]
22.
Zhang H, Schmeisser A, Garlichs CD, Plotze K,
Damme U, Mugge A, Daniel WG. Angiotensin II-induced
superoxide anion generation in human vascular
endothelial cells: role of membrane-bound
NADH-/NADPH-oxidases. Cardiovasc Res. 1999;44:215–222.
23.
Lang D, Mosfer SI, Shakesby A, Donaldson F,
Lewis MJ. Coronary microvascular endothelial
cell redox state in left ventricular
hypertrophy: the role of angiotensin II.
Circ Res. 2000;86:463–469.
24.
Marumo T, Schini-Kerth VB, Fisslthaler B, Busse
R. Platelet-derived growth factor–stimulated superoxide anion
production modulates activation of transcription factor
NF-B and expression of monocyte chemoattractant protein-1 in
human aortic smooth muscle cells. Circulation. 1997;96:2361–2367.
25.
Sundaresan M, Zu-Xi Y, Ferrans VJ, Irani K,
Finkel T. Requirement for generation of
H2O2 for
platelet-derived growth factor signal transduction.
Science. 1995;270:296–299.
26.
Bhunia AK, Arai T, Bulkley G, Chatterjee S.
Lactosylceramide mediates tumor necrosis factor--induced
intercellular adhesion molecule-1 (ICAM-1) expression and the adhesion
of neutrophils in human umbilical vein endothelial
cells. J Biol Chem. 1998;273:34349–34357.
27.
Meier B, Radeke HH, Selle S, Younes M, Sies H,
Resch K, Habermehl GG. Human fibroblasts release reactive oxygen
species in response to interleukin-1 or tumor necrosis factor-.
Biochem J. 1989;263:539–545.[Medline]
[Order article via Infotrieve]
28. Meier B. Regulation of the superoxide releasing system in human fibroblasts. Adv Exp Med Biol. 1996;387:113–116.[Medline] [Order article via Infotrieve]
29.
Howard AB, Alexander RW, Nerem RM, Griendling
KK, Taylor WR. Cyclic strain induces an oxidative stress in
endothelial cells. Am J Physiol. 1997;272:C421–C427.
30.
De Keulenaer GW, Chappell DC, Ishizaka N, Nerem
RM, Alexander RW, Griendling KK. Oscillatory and steady laminar shear
stress differentially affect human endothelial redox
state. Circ Res. 1998;82:1094–1101.
31.
Murasawa S, Mori Y, Nozawa Y, Gotoh N, Shibuya
M, Masaki H, Maruyama K, Tsutsumi Y, Moriguchi Y, Shibazaki Y, Tanaka
Y, Iwasaka T, Inada M, Matsubara H. Angiotensin II type 1
receptor–induced extracellular signal–regulated protein kinase
activation is mediated by
Ca2+/calmodulin-dependent
transactivation of epidermal growth factor receptor. Circ
Res. 1998;82:1338–1348.
32.
Eguchi S, Numaguchi K, Iwasaki H, Matsumoto T,
Yamakawa T, Utsunomiya H, Motley ED, Kawakatsu H, Owada KM, Hirata Y,
Marumo F, Inagami T. Calcium-dependent epidermal growth factor receptor
transactivation mediates the angiotensin II-induced
mitogen-activated protein kinase activation in vascular smooth
muscle cells. J Biol Chem. 1998;273:8890–8896.
33. Rao GN. Hydrogen peroxide induces complex formation of SHC-Grb2-SOS with receptor tyrosine kinase and activates ras and extracellular signal-regulated protein kinases group of mitogen activated protein kinases. Oncogene. 1996;13:713–719.[Medline] [Order article via Infotrieve]
34. Ushio-Fukai M, Griendling KK, Becker PL, Alexander RW. Role of reactive oxygen species in angiotensin II-induced transactivation of epidermal growth factor receptor in vascular smooth muscle cells. Circulation. 1999;100(suppl):I-263.
35.
Wang D, Yu X, Cohen RA, Brecher P. Distinct
effects of N-acetylcysteine and nitric oxide on
angiotensin II-induced epidermal growth factor receptor
phosphorylation and intracellular
Ca(2+) levels. J Biol Chem. 2000;275:12223–12230.
36.
Heeneman S, Haendeler J, Saito Y, Ishida M,
Berk BC. Angiotensin II induces transactivation of two
different populations of the PDGFß-receptor: key role for the
adaptor protein Shc. J Biol Chem. 2000;275:15926–15932.
37.
Marrero MB, Schieffer B, Paxton WG, Schieffer
E, Bernstein KE. Electroporation of pp60c-src
antibodies inhibits the angiotensin II activation of
phospholipase C-1 in rat aortic smooth muscle cells. J
Biol Chem. 1995;270:15734–15738.
38. Ishida T, Ishida M, Suero J, Takahashi M, Berk BC. Agonist-stimulated cytoskeletal reorganization and signal transduction at focal adhesions in vascular smooth muscle cells require c-Src. J Clin Invest. 1999;103:789–797.[Medline] [Order article via Infotrieve]
39.
Sayeski PP, Ali MS, Hawks K, Frank SJ,
Bernstein KE. The angiotensin II–dependent association of
Jak2 and c-Src requires the N-terminus of Jak2 and the
SH2 domain of c-Src. Circ Res. 1999;84:1332–1338.
40.
Abe JI, Takahashi M, Ishida M, Lee JD, Berk BC.
c-Src is required for oxidative stress-mediated activation of big
mitogen-activated protein kinase 1. J Biol
Chem. 1997;272:20389–20394.
41.
Lander HM, Ogiste JS, Teng KK, Novogrodsky A.
p21ras as a common signaling target of reactive free radicals and
cellular redox stress. J Biol Chem. 1995;270:21195–21198.
42.
Lander HM, Hajjar DP, Hempstead BL, Mirza UA,
Chait BT, Campbell S, Quilliam LA. A molecular redox switch on
p21(ras): structural basis for the nitric oxide-p21(ras) interaction.
J Biol Chem. 1997;272:4323–4326.
43.
Lander HM, Tauras JM, Ogiste JS, Hori O, Moss
RA, Schmidt AM. Activation of the receptor for advanced glycation end
products triggers a p21(ras)-dependent mitogen-activated
protein kinase pathway regulated by oxidant stress. J Biol
Chem. 1997;272:17810–17814.
44.
Deora AA, Win T, Vanhaesebroeck B, Lander HM. A
redox-triggered ras-effector interaction: recruitment of
phosphatidylinositol 3'-kinase to Ras by redox stress. J
Biol Chem. 1998;273:29923–29928.
45.
Ushio-Fukai M, Alexander RW, Akers M,
Griendling KK. p38 MAP kinase is a critical component of the
redox-sensitive signaling pathways by angiotensin II: role
in vascular smooth muscle cell hypertrophy. J
Biol Chem. 1998;273:15022–15029.
46.
Yoshizumi M, Abe J, Haendeler J, Huang Q, Berk
BC. Src and Cas mediate JNK activation but not ERK1/2 and p38 kinases
by reactive oxygen species. J Biol Chem. 2000;275:11706–11712.
47.
Abe J, Kusuhara M, Ulevitch RJ, Berk BC, Lee
J-D. Big mitogen-activated protein kinase 1 (BMK1) is a
redox-sensitive kinase. J Biol Chem. 1996;271:16586–16590.
48.
Zhang J, Jin N, Liu Y, Rhoades RA. Hydrogen
peroxide stimulates extracellular signal-regulated protein kinases in
pulmonary arterial smooth muscle cells.
Am J Respir Cell Mol Biol. 1998;19:324–332.
49.
Baas AS, Berk BC. Differential activation of
mitogen-activated protein kinases by
H2O2 and
O2- in vascular smooth muscle
cells. Circ Res. 1995;77:29–36.
50.
Viedt C, Soto U, Krieger-Brauer HI, Fei J,
Elsing C, Kubler W, Kreuzer J. Differential activation of
mitogen-activated protein kinases in smooth muscle cells by
angiotensin II: involvement of p22phox and reactive oxygen
species. Arterioscler Thromb Vasc Biol. 2000;20:940–948.
51. Shin EA, Kim KH, Han SI, Ha KS, Kim JH, Kang KI, Kim HD, Kang HS. Arachidonic acid induces the activation of the stress-activated protein kinase, membrane ruffling and H2O2 production via a small GTPase Rac1. FEBS Lett. 1999;452:355–359.[Medline] [Order article via Infotrieve]
52.
Huot J, Houle F, Marceau F, Landry J.
Oxidative-stress induced actin reorganization mediated by the p38
mitogen-activated protein kinase/heat shock protein 27 pathway
in vascular endothelial cells. Circ Res. 1997;80:383–392.
53.
Huot J, Houle F, Rousseau S, Deschesnes RG,
Shah GM, Landry J. SAPK2/p38-dependent F-actin reorganization regulates
early membrane blebbing during stress-induced apoptosis.
J Cell Biol. 1998;143:1361–1373.
54. Yeh LH, Park YJ, Hansalia RJ, Ahmed IS, Deshpande SS, Goldschmidt-Clermont PJ, Irani K, Alevriadou BR. Shear-induced tyrosine phosphorylation in endothelial cells requires Rac1-dependent production of ROS. Am J Physiol. 1999;276:C838–C847.
55. Clerk A, Michael A, Sugden PH. Stimulation of multiple mitogen-activated protein kinase subfamilies by oxidative stress and phosphorylation of the small heat shock protein, HSP25/27, in neonatal ventricular myocytes. Biochem J. 1998;333:581–589.
56. Coffer PJ, Jin J, Woodgett JR. Protein kinase B (c-Akt): a multifunctional mediator of phosphatidylinositol 3-kinase activation. Biochem J. 1998;335:1–13.
57.
Ushio-Fukai M, Alexander RW, Akers M, Yin Q,
Fujio Y, Walsh K, Griendling KK. Reactive oxygen species mediate the
activation of Akt/protein kinase B by angiotensin II in
vascular smooth muscle cells. J Biol Chem. 1999;274:22699–22704.
58. Shaw M, Cohen P, Alessi DR. The activation of protein kinase B by H2O2 or heat shock is mediated by phosphoinositide 3-kinase and not by mitogen-activated protein kinase-activated protein kinase-2. Biochem J. 1998;336:241–246.
59. Konishi H, Matsuzaki H, Tanaka M, Takemura Y, Kuroda S, Ono Y, Kikkawa U. Activation of protein kinase B (Akt/RAC-protein kinase) by cellular stress and its association with heat shock protein Hsp27. FEBS Lett. 1997;410:493–498.[Medline] [Order article via Infotrieve]
60.
Wang X, McCullough KD, Franke TF, Holbrook NJ.
Epidermal growth factor receptor-dependent akt activation by oxidative
stress enhances cell survival. J Biol Chem. 2000;275:14624–14631.
61.
Guy GR, Cairns J, Ng SB, Tan YH. Inactivation
of a redox-sensitive protein phosphatase during the early events of
tumor necrosis factor-interleukin-1 signal transduction. J
Biol Chem. 1993;268:2141–2148.
62. Freshney NW, Rawlinson L, Guesdon F, Jones E, Cowley S, Hsuan J, Saklatvala J. Interleukin-1 activates a novel protein kinase cascade that results in the phosphorylation of Hsp27. Cell. 1994;78:1039–1049.[Medline] [Order article via Infotrieve]
63. Rouse J, Cohen P, Trigon S, Morange M, Alonso-Llamazares A, Zamanillo D, Hunt T, Nebreda AR. A novel kinase cascade triggered by stress and heat shock that stimulates MAPKAP kinase-2 and phosphorylation of the small heat shock proteins. Cell. 1994;78:1027–1037.[Medline] [Order article via Infotrieve]
64. Alessi DR, Caudwell FB, Andjelkovic M, Hemmings BA, Cohen P. Molecular basis for the substrate specificity of protein kinase B: comparison with MAPKAP kinase-1 and p70 S6 kinase. FEBS Lett. 1996;399:333–338.[Medline] [Order article via Infotrieve]
65.
Hemmings BA. Akt signaling: linking membrane
events to life and death decisions. Science. 1997;275:628–630.
66.
Natarajan V, Taher MM, Roehm B, Parinandi NL,
Schmid HHO, Kiss Z, Garcia JGN. Activation of
endothelial cell phospholipase D by hydrogen peroxide
and fatty acid hydroperoxide. J Biol Chem. 1993;268:930–937.
67.
Abe JI, Berk BC. Fyn and JAK2 mediate ras
activation by reactive oxygen species. J Biol Chem. 1999;274:21003–21010.
68. Frank GD, Motley ED, Inagami T, Eguchi S. PYK2/CAKß represents a redox-sensitive tyrosine kinase in vascular smooth muscle cells. Biochem Biophys Res Commun. 2000;270:761–765.[Medline] [Order article via Infotrieve]
69. Simon AR, Rai U, Fanburg BL, Cochran BH. Activation of the JAK-STAT pathway by reactive oxygen species. Am J Physiol. 1998;275:C1640–C1652.
70.
Lu D, Maulik N, Moraru II, Kreutzer DL, Das DK.
Molecular adaptation of vascular endothelial cells to
oxidative stress. Am J Physiol. 1993;264:C715–C722.
71.
Arai T, Kelly SA, Brengman ML, Takano M, Smith
EH, Goldschmidt-Clermont PJ, Bulkley GB. Ambient but not incremental
oxidant generation affects intercellular adhesion molecule 1 induction
by tumour necrosis factor in endothelium.
Biochem J. 1998;331:853–861.
72.
Chen XL, Tummala PE, Olbrych MT, Alexander RW,
Medford RM. Angiotensin II induces monocyte chemoattractant
protein-1 gene expression in rat vascular smooth muscle cells.
Circ Res. 1998;83:952–959.
73. Spiecker M, Darius H, Kaboth K, Hübner F, Liao JK. Differential regulation of endothelial cell adhesion molecule expression by nitric oxide donors and antioxidants. J Leukoc Biol. 1998;63:732–739.[Abstract]
74.
Spiecker M, Peng HB, Liao JK. Inhibition of
endothelial vascular cell adhesion molecule-1
expression by nitric oxide involves the induction and nuclear
translocation of IB. J Biol Chem. 1997;272:30969–30974.
75.
Hong YH, Peng HB, La Fata V, Liao JK. Hydrogen
peroxide-mediated transcriptional induction of macrophage
colony-stimulating factor by TGF-ß1. J Immunol. 1997;159:2418–2423.
76.
Peng HB, Rajavashisth TB, Libby P, Liao JK.
Nitric oxide inhibits macrophage-colony stimulating factor gene
transcription in vascular endothelial cells.
J Biol Chem. 1995;270:17050–17055.
77.
Wung BS, Cheng JJ, Chao YJ, Hsieh HJ, Wang DL.
Modulation of Ras/Raf/extracellular signal-regulated kinase pathway by
reactive oxygen species is involved in cyclic strain–induced early
growth response-1 gene expression in endothelial cells.
Circ Res. 1999;84:804–812.
78.
Barchowsky A, Munro SR, Morana SJ, Vincenti MP,
Treadwell M. Oxidant-sensitive and
phosphorylation-dependent activation of NF-B
and AP-1 in endothelial cells. Am J
Physiol. 1995;269:L829–L836.
79. Rao GN, Alexander RW, Runge MS. Linoleic acid and its metabolites, hydroperoxyoctadecadienoic acids, stimulate c-fos, c-jun, and c-myc mRNA expression, mitogen-activated protein kinase activation, and growth in rat aortic smooth muscle cells. J Clin Invest. 1995;96:842–847.
80. Demple B. Redox signaling and gene control in the Escherichia coli sox RS oxidative stress regulon: a review. Gene. 1996;179:53–57.[Medline] [Order article via Infotrieve]
81.
Duh JL, Zhu H, Shertzer HG, Nebert DW, Puga A.
The y-box motif mediates redox-dependent transcriptional activation in
mouse cells. J Biol Chem. 1995;270:30499–30507.
82. Dalton TP, Shertzer HG, Puga A. Regulation of gene expression by reactive oxygen. Annu Rev Pharmacol Toxicol. 1999;39:67–101.[Medline] [Order article via Infotrieve]
83.
Huang LE, Arany Z, Livingston DM, Bunn HF.
Activation of hypoxia-inducible transcription factor depends
primarily on redox-sensitive stabilization of its subunit.
J Biol Chem. 1996;271:32253–32259.
84.
Hirota K, Matsui M, Iwata S, Nishiyama A,
Kenjiro M, Yodoi J. AP-1 transcriptional activity is regulated by a
direct association between thioredoxin and Ref-1. Proc Natl Acad
Sci U S A. 1997;94:3633–3638.
85.
Matthews JR, Wakasugi N, Virelizier JL, Yodoi
J, Hay RT. Thioredoxin regulates the DNA binding activity of
NF-ß by reduction of a disulphide bond involving cysteine 62.
Nucleic Acids Res. 1992;20:3821–3830.
86. Schwartz SM, Majesky MW, Dilley RJ. Vascular remodeling in hypertension and atherosclerosis. In: Laragh JH, Brenner BM, eds. Hypertension: Pathophysiology, Diagnosis and Management. New York, NY: Raven; 1990:521–539.
87.
Nakamura K, Fushimi K, Kouchi H, Mihara K,
Miyazaki M, Ohe T, Namba M. Inhibitory effects of
antioxidants on neonatal rat cardiac myocyte hypertrophy
induced by tumor necrosis factor- and angiotensin
II. Circulation. 1998;98:794–799.
88.
Scott NA, Cipolla GD, Ross CE, Dunn B, Martin
FH, Simonet L, Wilcox JN. Identification of a potential role for the
adventitia in vascular lesion formation after balloon overstretch
injury of porcine coronary arteries. Circulation. 1996;93:2178–2187.
89.
Brown MR, Miller FJ Jr, Li WG, Ellingson AN,
Mozena JD, Chatterjee P, Engelhardt JF, Zwacka RM, Oberley LW, Fang X,
Spector AA, Weintraub NL. Overexpression of human catalase inhibits
proliferation and promotes apoptosis in vascular smooth muscle
cells. Circ Res. 1999;85:524–533.
90.
Nishio E, Watanabe Y. The involvement of
reactive oxygen species and arachidonic acid in
1-adrenoceptor-induced smooth muscle cell proliferation and
migration. Br J Pharmacol. 1997;121:665–670.[Medline]
[Order article via Infotrieve]
91.
Pollman MJ, Hall JL, Gibbons GH. Determinants
of vascular smooth muscle cell apoptosis after balloon
angioplasty injury: influence of redox state and cell
phenotype. Circ Res. 1999;84:113–121.
92.
Nunes GL, Robinson K, Kalynych A, King SB III,
Sgoutas DS, Berk BC. Vitamins C and E inhibit
O2- production in the
pig coronary artery. Circulation. 1997;96:3593–3601.
93.
Nunes GL, Sgoutas DS, Redden RA, Sigman SR,
Gravanis MB, King SB III, Berk BC. Combination of vitamins C and E
alters the response to coronary balloon injury in the pig.
Arterioscler Thromb Vasc Biol. 1995;15:156–165.
94. Davies MG, Mason DP, Tran PK, Clowes AW. Inhibition of intimal hyperplasia by the p38 MAPK inhibitor, SB203580. FASEB J. 2000;14:A450.
95. Luscher TF, Noll G. Endothelial function as an end-point in interventional trials: concepts, methods and current data. J Hypertens. 1996;14(suppl):S111–S119.
96. Ohara Y, Peterson TE, Harrison DG. Hypercholesterolemia increases endothelial superoxide anion production. J Clin Invest. 1993;91:2546–2551.
97.
Mügge A, Elwell JH, Peterson TE, Hofmeyer
TG, Heistad DD, Harrison DG. Chronic treatment with
polyethylene-glycolated superoxide dismutase partially restores
endothelium-dependent vascular relaxations in
cholesterol-fed rabbits. Circ Res. 1991;69:1293–1300.
98. Keaney JF Jr, Xu A, Cunningham D, Jackson T, Frei B, Vita JA. Dietary probucol preserves endothelial function in cholesterol-fed rabbits by limiting vascular oxidative stress and superoxide generation. J Clin Invest. 1995;95:2520–2529.
99. Heitzer T, Wenzel U, Hink U, Krollner D, Skatchkov M, Stahl RA, MacHarzina R, Brasen JH, Meinertz T, Munzel T. Increased NAD(P)H oxidase-mediated superoxide production in renovascular hypertension: evidence for an involvement of protein kinase C. Kidney Int. 1999;55:252–260.[Medline] [Order article via Infotrieve]
100.
Somers MJ, Mavromatis K, Galis ZS, Harrison DG.
Vascular superoxide production and vasomotor function in
hypertension induced by deoxycorticosterone acetate-salt.
Circulation. 2000;101:1722–1728.
101.
Bech-Laursen J, Rajagopalan S, Galis Z, Tarpey
M, Freeman BA, Harrison DG. Role of superoxide in
angiotensin II–induced but not
catecholamine-induced hypertension. Circulation. 1997;95:588–593.
102.
Fukui T, Ishizaka N, Rajagopalan S, Laursen JB,
Capers Q IV, Taylor WR, Harrison DG, de Leon H, Wilcox JN, Griendling
KK. p22phox mRNA expression and NADPH oxidase activity are increased in
aortas from hypertensive rats. Circ Res. 1997;80:45–51.
103.
Capers QT, Alexander RW, Lou P, De Leon H,
Wilcox JN, Ishizaka N, Howard AB, Taylor WR. Monocyte chemoattractant
protein-1 expression in aortic tissues of hypertensive rats.
Hypertension. 1997;30:1397–1402.
104.
Capers Q, Laursen JB, Fukui T, Rajagopalan S,
Mori I, Lou P, Freeman BA, Berrington WR, Griendling KK, Harrison DG,
Runge MS, Alexander RW, Taylor WR. Vascular thrombin receptor
regulation in hypertensive rats. Circ Res. 1997;80:838–844.
105.
Tummala PE, Chen XL, Sundell CL, Laursen JB,
Hammes CP, Alexander RW, Harrison DG, Medford RM.
Angiotensin II induces vascular cell adhesion molecule-1
expression in rat vasculature: a potential link between the
renin-angiotensin system and
atherosclerosis. Circulation. 1999;100:1223–1229.
106.
De Keulenaer GW, Ushio-Fukai M, Yin Q, Chung AB,
Lyons PR, Ishizaka N, Rengarajan K, Taylor WR, Alexander RW, Griendling
KK. Convergence of redox-sensitive and mitogen-activated
protein kinase signaling pathways in tumor necrosis
factor-–mediated monocyte chemoattractant protein-1 induction
in vascular smooth muscle cells. Arterioscler Thromb Vasc
Biol. 2000;20:385–391.
107. Marui N, Offerman M, Swerlick R, Kunsch C, Rosen CA, Ahmad M, Alexander RW, Medford RM. Vascular cell-adhesion molecule-1 (VCAM-1) gene-transcription and expression are regulated through an antioxidant sensitive mechanism in human vascular endothelial cells. J Clin Invest. 1993;92:1866–1874.
108.
Galis ZS, Muszynski M, Sukhova GK,
Simon-Morrissey E, Unemori EN, Lark MW, Amento E, Libby P.
Cytokine-stimulated human vascular smooth muscle cells
synthesize a complement of enzymes required for extracellular matrix
digestion. Circ Res. 1994;75:181–189.
109. Galis ZS, Sukhova GK, Lark MW, Libby P. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Invest. 1994;94:2493–2503.
110. Rajagopalan S, Meng XP, Ramasamy S, Harrison DG, Galis ZS. Reactive oxygen species produced by macrophage-derived foam cells regulate the activity of vascular matrix metalloproteinases in vitro. J Clin Invest. 1996;98:2572–2579.[Medline] [Order article via Infotrieve]
111.
Galis ZS, Asanuma K, Godin D, Meng X.
N-acetylcysteine decreases the matrix-degrading capacity of
macrophage-derived foam cells: new target for antioxidant
therapy? Circulation. 1998;97:2445–2453.
112.
Jones SA, O’Donnell VB, Wood JD, Broughton JP,
Hughes EJ, Jones OTG. Expression of phagocyte NADPH oxidase components
in human endothelial cells. Am J
Physiol. 1996;271:H1626–H1634.
113.
Bayraktutan U, Draper N, Lang D, Shah AM.
Expression of functional neutrophil-type NADPH oxidase in cultured rat
coronary microvascular endothelial cells.
Cardiovasc Res. 1998;38:256–262.
114.
Pagano PJ, Clark JK, Cifuentes-Pagano ME, Clark
SM, Callis GM, Quinn MT. Localization of a constitutively active,
phagocyte-like NADPH oxidase in rabbit aortic adventitia: enhancement
by angiotensin II. Proc Natl Acad Sci U S A. 1997;94:14483–14488.
115.
Fukui T, Lassègue B, Kai H, Alexander RW,
Griendling KK. cDNA cloning and mRNA expression of cytochrome
b558 -subunit in rat vascular smooth muscle
cells. Biochim Biophys Acta. 1995;1231:215–219.[Medline]
[Order article via Infotrieve]
116.
Khan BV, Harrison DG, Olbrych MT, Alexander RW,
Medford RM. Nitric oxide regulates VCAM-1 gene expression and
redox-sensitive transcriptional events in human vascular
endothelial cells. Proc Natl Acad Sci
U S A. 1996;93:9114–9119.
117. DeCaterina R, Libby P, Peng HB, Thannickal VJ, Rajavashisth TB, Gimbrone MA Jr, Shin WS, Liao JK. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J Clin Invest. 1995;96:60–68.
118. Suzuki Y, Wang W, Vu TH, Raffin TA. Effect of NADPH oxidase inhibition on endothelial cell ELAM-1 mRNA expression. Biochem Biophys Res Commun. 1992;184:1339–1343.[Medline] [Order article via Infotrieve]
119.
Satriano JA, Shuldiner M, Hora K, Xing Y, Shan
Z, Schlondorff D. Oxygen radicals as second messengers for expression
of the monocyte chemoattractant protein, JE/MCP-1, and the monocyte
colony-stimulating factor, CSF-1, in response to tumor necrosis
factor- and immunoglobulin G: evidence for involvement of
reduced nicotinamide adenine dinucleotide phosphate
(NADPH)-dependent oxidase. J Clin Invest. 1993;92:1564–1571.
120. Lopez-Ongil S, Hernandez-Perera O, Navarro-Antolin J, Perez de Lema G, Rodriguez-Puyol M, Lamas S, Rodriguez-Puyol D. Role of reactive oxygen species in the signalling cascade of cyclosporine A-mediated up-regulation of eNOS in vascular endothelial cells. Br J Pharmacol. 1998;124:447–454.[Medline] [Order article via Infotrieve]
121.
Tetsuka T, Baier LD, Morrison AR. Antioxidants
inhibit interleukin-1-induced cyclooxygenase and
nitric-oxide synthase expression in rat mesangial cells.
J Biol Chem. 1996;271:11689–11693.
122.
Das KC, Lewis-Molock Y, White CW. Elevation of
manganese superoxide dismutase gene expression by thioredoxin.
Am J Respir Cell Mol Biol. 1997;17:713–726.
123. Wang LJ, Lee TS, Lee FY, Pai RC, Chau LY. Expression of heme oxygenase-1 in atherosclerotic lesions. Am J Pathol. 1998;152:711–720.[Abstract]
124.
Hartsfield CL, Alam J, Choi AM. Transcriptional
regulation of the heme oxygenase 1 gene by pyrrolidine
dithiocarbamate. FASEB J. 1998;12:1675–1682.
125.
Aucoin MM, Barhoumi R, Kochevar DT, Granger HJ,
Burghardt RC. Oxidative injury of coronary venular
endothelial cells depletes intracellular glutathione
and induces HSP 70 mRNA. Am J Physiol. 1995;268:H1651–H1658.
126.
Mietus-Snyder M, Glass CK, Pitas RE.
Transcriptional activation of scavenger receptor expression in human
smooth muscle cells requires AP-1/c-Jun and C/EBPß.
Arterioscler Thromb Vasc Biol. 1998;18:1440–1449.
127.
Shono T, Ono M, Izumi H, Jimi SI, Matsushima K,
Okamoto T, Kohno K, Kuwano M. Involvement of the transcription factor
NF-B in tubular morphogenesis of human microvascular
endothelial cells by oxidative stress. Mol Cell
Biol. 1996;16:4231–4239.[Abstract]
128. Kayanoki Y, Higashiyama S, Suzuki K, Asahi M, Kawata S, Matsuzawa Y, Taniguchi N. The requirement of both intracellular reactive oxygen species and intracellular calcium elevation for the induction of heparin-binding EGF-like growth factor in vascular endothelial cells and smooth muscle cells. Biochem Biophys Res Commun. 1999;259:50–55.[Medline] [Order article via Infotrieve]
129.
Che W, Asahi M, Takahashi M, Kaneto H, Okado A,
Higashiyama S, Taniguchi N. Selective induction of heparin-binding
epidermal growth factor-like growth factor by methylglyoxal and
3-deoxyglucosone in rat aortic smooth muscle cells: the involvement of
reactive oxygen species formation and a possible implication for
atherogenesis in diabetes. J Biol Chem. 1997;272:18453–18459.
130.
Xie Z, Kometiani P, Liu J, Li J, Shapiro JI, Askari A.
Intracellular reactive oxygen species mediate the linkage of
Na+/K+-ATPase to
hypertrophy and its marker genes in cardiac myocytes.
J Biol Chem. 1999;274:19323–19328.
131. Chua CC, Hamdy RC, Chua BH. Upregulation of vascular endothelial growth factor by H2O2 in rat heart endothelial cells. Free Radic Biol Med. 1998;25:891–897.[Medline] [Order article via Infotrieve]
132.
Ruef J, Hu ZY, Yin LY, Wu Y, Hanson SR, Kelly
AB, Harker LA, Rao GN, Runge MS, Patterson C. Induction of vascular
endothelial growth factor in balloon-injured baboon
arteries. Circ Res. 1997;81:24–33.
This article has been cited by other articles:
 |
|
 |
|
  J. S. Isenberg and S. Shiva Vasoconstriction: tightening the noose through MMPs Cardiovasc Res, December 1, 2009; 84(3): 339 - 340. [Full Text] [PDF]
|
|
|
|
 |
|
 L. M. Fan, L. Teng, and J.-M. Li Knockout of p47phox Uncovers a Critical Role of p40phox in Reactive Oxygen Species Production in Microvascular Endothelial Cells Arterioscler Thromb Vasc Biol, October 1, 2009; 29(10): 1651 - 1656. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Ikeda, K.-i. Aihara, S. Yoshida, T. Sato, S. Yagi, T. Iwase, Y. Sumitomo, T. Ise, K. Ishikawa, H. Azuma, et al. Androgen-Androgen Receptor System Protects against Angiotensin II-Induced Vascular Remodeling Endocrinology, June 1, 2009; 150(6): 2857 - 2864. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Reed, B. Potter, E. Smith, R. Jadhav, P. Villalta, H. Jo, and P. Rocic Redox-sensitive Akt and Src regulate coronary collateral growth in metabolic syndrome Am J Physiol Heart Circ Physiol, June 1, 2009; 296(6): H1811 - H1821. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. E. Handy, E. Lubos, Y. Yang, J. D. Galbraith, N. Kelly, Y.-Y. Zhang, J. A. Leopold, and J. Loscalzo Glutathione Peroxidase-1 Regulates Mitochondrial Function to Modulate Redox-dependent Cellular Responses J. Biol. Chem., May 1, 2009; 284(18): 11913 - 11921. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Ponnuchamy and R. A. Khalil Cellular mediators of renal vascular dysfunction in hypertension Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2009; 296(4): R1001 - R1018. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. R. Collins, C. J. Lyon, X. Xia, J. Z. Liu, R. K. Tangirala, F. Yin, R. Boyadjian, A. Bikineyeva, D. Pratico, D. G. Harrison, et al. Age-Accelerated Atherosclerosis Correlates With Failure to Upregulate Antioxidant Genes Circ. Res., March 27, 2009; 104(6): e42 - e54. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Tanaka, K. Sasaki, R. Kamata, Y. Hoshino, K. Yanagihara, and R. Sakai A Novel RNA-Binding Protein, Ossa/C9orf10, Regulates Activity of Src Kinases To Protect Cells from Oxidative Stress-Induced Apoptosis Mol. Cell. Biol., January 15, 2009; 29(2): 402 - 413. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. N. Lavrentyev and K. U. Malik High glucose-induced Nox1-derived superoxides downregulate PKC-{beta}II, which subsequently decreases ACE2 expression and ANG(1-7) formation in rat VSMCs Am J Physiol Heart Circ Physiol, January 1, 2009; 296(1): H106 - H118. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Barabutis and A. V. Schally Antioxidant activity of growth hormone-releasing hormone antagonists in LNCaP human prostate cancer line PNAS, December 23, 2008; 105(51): 20470 - 20475. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. A. Knock, V. A. Snetkov, Y. Shaifta, S. Drndarski, J. P.T. Ward, and P. I. Aaronson Role of src-family kinases in hypoxic vasoconstriction of rat pulmonary artery Cardiovasc Res, December 1, 2008; 80(3): 453 - 462. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Jakob, P. Schroeder, M. Lukosz, N. Buchner, I. Spyridopoulos, J. Altschmied, and J. Haendeler Nuclear Protein Tyrosine Phosphatase Shp-2 Is One Important Negative Regulator of Nuclear Export of Telomerase Reverse Transcriptase J. Biol. Chem., November 28, 2008; 283(48): 33155 - 33161. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Matsuno, Y. Ito, T. Ohashi, M. Morise, N. Takeda, K. Shimokata, K. Imaizumi, H. Kume, and Y. Hasegawa Dual Pathway Activated by tert-Butyl Hydroperoxide in Human Airway Anion Secretion J. Pharmacol. Exp. Ther., November 1, 2008; 327(2): 453 - 464. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Liu, L. Gao, S. K. Roy, K. G. Cornish, and I. H. Zucker Role of Oxidant Stress on AT1 Receptor Expression in Neurons of Rabbits With Heart Failure and in Cultured Neurons Circ. Res., July 18, 2008; 103(2): 186 - 193. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Haurani, M. E. Cifuentes, A. D. Shepard, and P. J. Pagano Nox4 Oxidase Overexpression Specifically Decreases Endogenous Nox4 mRNA and Inhibits Angiotensin II-Induced Adventitial Myofibroblast Migration Hypertension, July 1, 2008; 52(1): 143 - 149. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Mollace, S. Ragusa, I. Sacco, C. Muscoli, F. Sculco, V. Visalli, E. Palma, S. Muscoli, L. Mondello, P. Dugo, et al. The Protective Effect of Bergamot Oil Extract on Lecitine-like OxyLDL Receptor-1 Expression in Balloon Injury-related Neointima Formation Journal of Cardiovascular Pharmacology and Therapeutics, June 1, 2008; 13(2): 120 - 129. [Abstract] [PDF]
|
|
|
|
 |
|
 N. Sud, S. M. Wells, S. Sharma, D. A. Wiseman, J. Wilham, and S. M. Black Asymmetric dimethylarginine inhibits HSP90 activity in pulmonary arterial endothelial cells: role of mitochondrial dysfunction Am J Physiol Cell Physiol, June 1, 2008; 294(6): C1407 - C1418. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. G. DeMarco, J. Habibi, A. T. Whaley-Connell, R. I. Schneider, R. L. Heller, J. P. Bosanquet, M. R. Hayden, K. Delcour, S. A. Cooper, B. T. Andresen, et al. Oxidative stress contributes to pulmonary hypertension in the transgenic (mRen2)27 rat Am J Physiol Heart Circ Physiol, June 1, 2008; 294(6): H2659 - H2668. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Takahashi, E. Suzuki, R. Takeda, S. Oba, H. Nishimatsu, K. Kimura, T. Nagano, R. Nagai, and Y. Hirata Angiotensin II and tumor necrosis factor-{alpha} synergistically promote monocyte chemoattractant protein-1 expression: roles of NF-{kappa}B, p38, and reactive oxygen species Am J Physiol Heart Circ Physiol, June 1, 2008; 294(6): H2879 - H2888. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. E. Herbert, Y. Mistry, R. Hastings, T. Poolman, L. Niklason, and B. Williams Angiotensin II-Mediated Oxidative DNA Damage Accelerates Cellular Senescence in Cultured Human Vascular Smooth Muscle Cells via Telomere-Dependent and Independent Pathways Circ. Res., February 1, 2008; 102(2): 201 - 208. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. M. Paravicini and R. M. Touyz NADPH Oxidases, Reactive Oxygen Species, and Hypertension: Clinical implications and therapeutic possibilities Diabetes Care, February 1, 2008; 31(Supplement_2): S170 - S180. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Choi, T. L. Leto, L. Hunyady, K. J. Catt, Y. S. Bae, and S. G. Rhee Mechanism of Angiotensin II-induced Superoxide Production in Cells Reconstituted with Angiotensin Type 1 Receptor and the Components of NADPH Oxidase J. Biol. Chem., January 4, 2008; 283(1): 255 - 267. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. W.T. Liu and P. L. Huang Cardiovascular roles of nitric oxide: A review of insights from nitric oxide synthase gene disrupted mice Cardiovasc Res, January 1, 2008; 77(1): 19 - 29. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Erusalimsky and S. Moncada Nitric Oxide and Mitochondrial Signaling: From Physiology to Pathophysiology Arterioscler Thromb Vasc Biol, December 1, 2007; 27(12): 2524 - 2531. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L.-J. Min, M. Mogi, J. Iwanami, J.-M. Li, A. Sakata, T. Fujita, K. Tsukuda, M. Iwai, and M. Horiuchi Cross-talk between aldosterone and angiotensin II in vascular smooth muscle cell senescence Cardiovasc Res, December 1, 2007; 76(3): 506 - 516. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Adachi, M. Yamamoto, and M. Suematsu Targeting NAD(P)H Oxidase: Ets-1 Regulates p47phox Circ. Res., November 9, 2007; 101(10): 962 - 964. [Full Text] [PDF]
|
|
|
|
|
|
W. Ni, Y. Zhan, H. He, E. Maynard, J. A. Balschi, and P. Oettgen Ets-1 Is a Critical Transcriptional Regulator of Reactive Oxygen Species and p47phox Gene Expression in Response to Angiotensin II Circ. Res., November 9, 2007; 101(10): 985 - 994. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Haurani and P. J. Pagano Adventitial fibroblast reactive oxygen species as autacrine and paracrine mediators of remodeling: Bellwether for vascular disease? Cardiovasc Res, September 1, 2007; 75(4): 679 - 689. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P. Luyendyk, J. D. Piper, M. Tencati, K. V. Reddy, T. Holscher, R. Zhang, J. Luchoomun, X. Chen, W. Min, C. Kunsch, et al. A Novel Class of Antioxidants Inhibit LPS Induction of Tissue Factor by Selective Inhibition of the Activation of ASK1 and MAP Kinases Arterioscler Thromb Vasc Biol, August 1, 2007; 27(8): 1857 - 1863. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Pirillo, P. Uboldi, G. Pappalardo, H. Kuhn, and A. L. Catapano Modification of HDL3 by mild oxidative stress increases ATP-binding cassette transporter 1-mediated cholesterol efflux Cardiovasc Res, August 1, 2007; 75(3): 566 - 574. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Kitayama, F. M. Faraci, S. R. Lentz, and D. D. Heistad Cerebral Vascular Dysfunction During Hypercholesterolemia Stroke, July 1, 2007; 38(7): 2136 - 2141. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. S. Barbieri and B. B. Weksler Tobacco smoke cooperates with interleukin-1{beta} to alter {beta}-catenin trafficking in vascular endothelium resulting in increased permeability and induction of cyclooxygenase-2 expression in vitro and in vivo FASEB J, June 1, 2007; 21(8): 1831 - 1843. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Ding, A. Chapman, R. Boyd, and H. D. Wang ERK activation contributes to regulation of spontaneous contractile tone via superoxide anion in isolated rat aorta of angiotensin II-induced hypertension Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H2997 - H3005. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Yusof, K. Kamada, F. Spencer Gaskin, and R. J. Korthuis Angiotensin II mediates postischemic leukocyte-endothelial interactions: role of calcitonin gene-related peptide Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H3032 - H3037. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Larghero, R. Vene, S. Minghelli, G. Travaini, M. Morini, N. Ferrari, U. Pfeffer, D. M. Noonan, A. Albini, and R. Benelli Biological assays and genomic analysis reveal lipoic acid modulation of endothelial cell behavior and gene expression Carcinogenesis, May 1, 2007; 28(5): 1008 - 1020. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. N. Mayorov Brain superoxide as a key regulator of the cardiovascular response to emotional stress in rabbits Exp Physiol, May 1, 2007; 92(3): 471 - 479. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Alcaraz, D. Iyu, N. M. Atucha, J. Garcia-Estan, and M. C. Ortiz Vitamin E supplementation reverses renal altered vascular reactivity in chronic bile duct-ligated rats Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2007; 292(4): R1486 - R1493. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Liu, T. Shimosawa, H. Matsui, F. Meng, S. C. Supowit, D. J. DiPette, K. Ando, and T. Fujita Adrenomedullin inhibits angiotensin II-induced oxidative stress via Csk-mediated inhibition of Src activity Am J Physiol Heart Circ Physiol, April 1, 2007; 292(4): H1714 - H1721. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Chakraborty, H. Brooks, P. Zhang, W. Smith, M. R. McReynolds, J. B. Hoying, R. Bick, L. Truong, B. Poindexter, H. Lan, et al. Stanniocalcin-1 regulates endothelial gene expression and modulates transendothelial migration of leukocytes Am J Physiol Renal Physiol, February 1, 2007; 292(2): F895 - F904. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Bedard and K.-H. Krause The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology Physiol Rev, January 1, 2007; 87(1): 245 - 313. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Thakali, L. Davenport, G. D. Fink, and S. W. Watts Cyclooxygenase, p38 Mitogen-Activated Protein Kinase (MAPK), Extracellular Signal-Regulated Kinase MAPK, Rho Kinase, and Src Mediate Hydrogen Peroxide-Induced Contraction of Rat Thoracic Aorta and Vena Cava J. Pharmacol. Exp. Ther., January 1, 2007; 320(1): 236 - 243. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Orosz, A. Csiszar, N. Labinskyy, K. Smith, P. M. Kaminski, P. Ferdinandy, M. S. Wolin, A. Rivera, and Z. Ungvari Cigarette smoke-induced proinflammatory alterations in the endothelial phenotype: role of NAD(P)H oxidase activation Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H130 - H139. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F.-Y. Lin, Y.-H. Chen, Y.-W. Lin, J.-S. Tsai, J.-W. Chen, H.-J. Wang, Y.-L. Chen, C.-Y. Li, and S.-J. Lin The Role of Human Antigen R, an RNA-binding Protein, in Mediating the Stabilization of Toll-Like Receptor 4 mRNA Induced by Endotoxin: A Novel Mechanism Involved in Vascular Inflammation Arterioscler Thromb Vasc Biol, December 1, 2006; 26(12): 2622 - 2629. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F.-Y. Lin, Y.-H. Chen, J.-S. Tasi, J.-W. Chen, T.-L. Yang, H.-J. Wang, C.-Y. Li, Y.-L. Chen, and S.-J. Lin Endotoxin Induces Toll-Like Receptor 4 Expression in Vascular Smooth Muscle Cells via NADPH Oxidase Activation and Mitogen-Activated Protein Kinase Signaling Pathways Arterioscler Thromb Vasc Biol, December 1, 2006; 26(12): 2630 - 2637. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Ushio-Fukai and R. W. Alexander Caveolin-Dependent Angiotensin II Type 1 Receptor Signaling in Vascular Smooth Muscle Hypertension, November 1, 2006; 48(5): 797 - 803. [Full Text] [PDF]
|
|
|
|
|
|
C. E. Murdoch, M. Zhang, A. C. Cave, and A. M. Shah NADPH oxidase-dependent redox signalling in cardiac hypertrophy, remodelling and failure Cardiovasc Res, July 15, 2006; 71(2): 208 - 215. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. E. Clempus and K. K. Griendling Reactive oxygen species signaling in vascular smooth muscle cells Cardiovasc Res, July 15, 2006; 71(2): 216 - 225. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. M. Paravicini and R. M. Touyz Redox signaling in hypertension Cardiovasc Res, July 15, 2006; 71(2): 247 - 258. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. V. Ramana, A. Bhatnagar, S. Srivastava, U. C. Yadav, S. Awasthi, Y. C. Awasthi, and S. K. Srivastava Mitogenic Responses of Vascular Smooth Muscle Cells to Lipid Peroxidation-derived Aldehyde 4-Hydroxy-trans-2-nonenal (HNE): ROLE OF ALDOSE REDUCTASE-CATALYZED REDUCTION OF THE HNE-GLUTATHIONE CONJUGATES IN REGULATING CELL GROWTH J. Biol. Chem., June 30, 2006; 281(26): 17652 - 17660. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. Pagano and M. J. Haurani Vascular Cell Locomotion: Osteopontin, NADPH Oxidase, and Matrix Metalloproteinase-9 Circ. Res., June 23, 2006; 98(12): 1453 - 1455. [Full Text] [PDF]
|
|
|
|
|
|
M. Weaver, J. Liu, D. Pimentel, D. J. Reddy, P. Harding, E. L. Peterson, and P. J. Pagano Adventitial delivery of dominant-negative p67phox attenuates neointimal hyperplasia of the rat carotid artery Am J Physiol Heart Circ Physiol, May 1, 2006; 290(5): H1933 - H1941. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Ardanaz and P. J. Pagano Hydrogen peroxide as a paracrine vascular mediator: regulation and signaling leading to dysfunction. Experimental Biology and Medicine, March 1, 2006; 231(3): 237 - 251. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Polikandriotis, H. L. Rupnow, S. C. Elms, R. E. Clempus, D. J. Campbell, R. L. Sutliff, L. A. S. Brown, D. M. Guidot, and C. M. Hart Chronic Ethanol Ingestion Increases Superoxide Production and NADPH Oxidase Expression in the Lung Am. J. Respir. Cell Mol. Biol., March 1, 2006; 34(3): 314 - 319. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Cave, D. Grieve, S. Johar, M. Zhang, and A. M Shah NADPH oxidase-derived reactive oxygen species in cardiac pathophysiology Phil Trans R Soc B, December 29, 2005; 360(1464): 2327 - 2334. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Cheng, W. Cao, C. Fiocchi, J. Behar, P. Biancani, and K. M. Harnett In vitro model of acute esophagitis in the cat Am J Physiol Gastrointest Liver Physiol, November 1, 2005; 289(5): G860 - G869. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Li, G. Zhang, F.-X. Yi, A.-P. Zou, and P.-L. Li Activation of NAD(P)H oxidase by outward movements of H+ ions in renal medullary thick ascending limb of Henle Am J Physiol Renal Physiol, November 1, 2005; 289(5): F1048 - F1056. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Suvorava, N. Lauer, S. Kumpf, R. Jacob, W. Meyer, and G. Kojda Endogenous Vascular Hydrogen Peroxide Regulates Arteriolar Tension In Vivo Circulation, October 18, 2005; 112(16): 2487 - 2495. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. H.H. Chan, K.-S. Hsu, C.-C. Huang, L.-L. Wang, C.-C. Ou, and J. Y.H. Chan NADPH Oxidase-Derived Superoxide Anion Mediates Angiotensin II-Induced Pressor Effect via Activation of p38 Mitogen-Activated Protein Kinase in the Rostral Ventrolateral Medulla Circ. Res., October 14, 2005; 97(8): 772 - 780. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. De Ciuceis, F. Amiri, P. Brassard, D. H. Endemann, R. M. Touyz, and E. L. Schiffrin Reduced Vascular Remodeling, Endothelial Dysfunction, and Oxidative Stress in Resistance Arteries of Angiotensin II-Infused Macrophage Colony-Stimulating Factor-Deficient Mice: Evidence for a Role in Inflammation in Angiotensin-Induced Vascular Injury Arterioscler Thromb Vasc Biol, October 1, 2005; 25(10): 2106 - 2113. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Zuo, M. Ushio-Fukai, S. Ikeda, L. Hilenski, N. Patrushev, and R. W. Alexander Caveolin-1 Is Essential for Activation of Rac1 and NAD(P)H Oxidase After Angiotensin II Type 1 Receptor Stimulation in Vascular Smooth Muscle Cells: Role in Redox Signaling and Vascular Hypertrophy Arterioscler Thromb Vasc Biol, September 1, 2005; 25(9): 1824 - 1830. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. K. Jagadeesha, T. E. Lindley, J. DeLeon, R. V. Sharma, F. Miller, and R. C. Bhalla Tempol therapy attenuates medial smooth muscle cell apoptosis and neointima formation after balloon catheter injury in carotid artery of diabetic rats Am J Physiol Heart Circ Physiol, September 1, 2005; 289(3): H1047 - H1053. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Berg Increased counteracting effect of eNOS and nNOS on an {alpha}1-adrenergic rise in total peripheral vascular resistance in spontaneous hypertensive rats Cardiovasc Res, September 1, 2005; 67(4): 736 - 744. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. W. Zmijewski, D. R. Moellering, C. L. Goffe, A. Landar, A. Ramachandran, and V. M. Darley-Usmar Oxidized LDL induces mitochondrially associated reactive oxygen/nitrogen species formation in endothelial cells Am J Physiol Heart Circ Physiol, August 1, 2005; 289(2): H852 - H861. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. L. Huang Unraveling the Links Between Diabetes, Obesity, and Cardiovascular Disease Circ. Res., June 10, 2005; 96(11): 1129 - 1131. [Full Text] [PDF]
|
|
|
|
 |
|
 G. Desideri, M. De Simone, L. Iughetti, T. Rosato, M. L. Iezzi, M. C. Marinucci, V. Cofini, G. Croce, G. Passacquale, S. Necozione, et al. Early Activation of Vascular Endothelial Cells and Platelets in Obese Children J. Clin. Endocrinol. Metab., June 1, 2005; 90(6): 3145 - 3152. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Akishita, K. Nagai, H. Xi, W. Yu, N. Sudoh, T. Watanabe, M. Ohara-Imaizumi, S. Nagamatsu, K. Kozaki, M. Horiuchi, et al. Renin-Angiotensin System Modulates Oxidative Stress-Induced Endothelial Cell Apoptosis in Rats Hypertension, June 1, 2005; 45(6): 1188 - 1193. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Krotz, B. Engelbrecht, M. A. Buerkle, F. Bassermann, H. Bridell, T. Gloe, J. Duyster, U. Pohl, and H.-Y. Sohn The Tyrosine Phosphatase, SHP-1, Is a Negative Regulator of Endothelial Superoxide Formation J. Am. Coll. Cardiol., May 17, 2005; 45(10): 1700 - 1706. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. M. Griffith, A. T. Chaytor, L. M. Bakker, and D. H. Edwards 5-Methyltetrahydrofolate and tetrahydrobiopterin can modulate electrotonically mediated endothelium-dependent vascular relaxation PNAS, May 10, 2005; 102(19): 7008 - 7013. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. I. Mendez, W. J. Nicholson, and W. R. Taylor SOD Isoforms and Signaling in Blood Vessels: Evidence for the Importance of ROS Compartmentalization Arterioscler Thromb Vasc Biol, May 1, 2005; 25(5): 887 - 888. [Full Text] [PDF]
|
|
|
|
|
|
C. Kunsch, J. Luchoomun, X.-l. Chen, G. L. Dodd, K. S. Karu, C. Q. Meng, E. M. Marino, L. K. Olliff, J. D. Piper, F.-H. Qiu, et al. J. Pharmacol. Exp. Ther., May 1, 2005; 313(2): 492 - 501. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P.-C. Lee, I-C. Ho, and T.-C. Lee Oxidative Stress Mediates Sodium Arsenite-Induced Expression of Heme Oxygenase-1, Monocyte Chemoattractant Protein-1, and Interleukin-6 in Vascular Smooth Muscle Cells Toxicol. Sci., May 1, 2005; 85(1): 541 - 550. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Ago, T. Kitazono, J. Kuroda, Y. Kumai, M. Kamouchi, H. Ooboshi, M. Wakisaka, T. Kawahara, K. Rokutan, S. Ibayashi, et al. NAD(P)H Oxidases in Rat Basilar Arterial Endothelial Cells Stroke, May 1, 2005; 36(5): 1040 - 1046. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Cai NAD(P)H Oxidase-Dependent Self-Propagation of Hydrogen Peroxide and Vascular Disease Circ. Res., April 29, 2005; 96(8): 818 - 822. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Rahmani, J. T. Read, J. M. Carthy, P. C. McDonald, B. W. Wong, M. Esfandiarei, X. Si, Z. Luo, H. Luo, P. S. Rennie, et al. Regulation of the Versican Promoter by the {beta}-Catenin-T-cell Factor Complex in Vascular Smooth Muscle Cells J. Biol. Chem., April 1, 2005; 280(13): 13019 - 13028. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Tsuda, M. Iwai, J.-M. Li, H.-S. Li, L.-J. Min, A. Ide, M. Okumura, J. Suzuki, M. Mogi, H. Suzuki, et al. Inhibitory Effects of AT1 Receptor Blocker, Olmesartan, and Estrogen on Atherosclerosis Via Anti-Oxidative Stress Hypertension, April 1, 2005; 45(4): 545 - 551. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. Touyz, C. Mercure, Y. He, D. Javeshghani, G. Yao, G. E. Callera, A. Yogi, N. Lochard, and T. L. Reudelhuber Angiotensin II-Dependent Chronic Hypertension and Cardiac Hypertrophy Are Unaffected by gp91phox-Containing NADPH Oxidase Hypertension, April 1, 2005; 45(4): 530 - 537. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Djordjevic, R. S. BelAiba, S. Bonello, J. Pfeilschifter, J. Hess, and A. Gorlach Human Urotensin II Is a Novel Activator of NADPH Oxidase in Human Pulmonary Artery Smooth Muscle Cells Arterioscler Thromb Vasc Biol, March 1, 2005; 25(3): 519 - 525. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. E. Haskew-Layton, A. A. Mongin, and H. K. Kimelberg Hydrogen Peroxide Potentiates Volume-sensitive Excitatory Amino Acid Release via a Mechanism Involving Ca2+/Calmodulin-dependent Protein Kinase II J. Biol. Chem., February 4, 2005; 280(5): 3548 - 3554. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Houston, M. A. Julien, S. Parthasarathy, and E. L. Chaikof Oxidized linoleic acid regulates expression and shedding of syndecan-4 Am J Physiol Cell Physiol, February 1, 2005; 288(2): C458 - C466. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. M. Dourron, G. M. Jacobson, J. L. Park, J. Liu, D. J. Reddy, M. L. Scheel, and P. J. Pagano Perivascular gene transfer of NADPH oxidase inhibitor suppresses angioplasty-induced neointimal proliferation of rat carotid artery Am J Physiol Heart Circ Physiol, February 1, 2005; 288(2): H946 - H953. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Lau, H. Mollnau, J. P. Eiserich, B. A. Freeman, A. Daiber, U. M. Gehling, J. Brummer, V. Rudolph, T. Munzel, T. Heitzer, et al. Myeloperoxidase mediates neutrophil activation by association with CD11b/CD18 integrins PNAS, January 11, 2005; 102(2): 431 - 436. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Hongpaisan, C. A. Winters, and S. B. Andrews Strong Calcium Entry Activates Mitochondrial Superoxide Generation, Upregulating Kinase Signaling in Hippocampal Neurons J. Neurosci., December 1, 2004; 24(48): 10878 - 10887. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. N. Bratz and N. L. Kanagy Nitric oxide synthase-inhibition hypertension is associated with altered endothelial cyclooxygenase function Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2394 - H2401. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-W. Chen, F.-Y. Lin, Y.-H. Chen, T.-C. Wu, Y.-L. Chen, and S.-J. Lin Carvedilol Inhibits Tumor Necrosis Factor-{alpha}-Induced Endothelial Transcription Factor Activation, Adhesion Molecule Expression, and Adhesiveness to Human Mononuclear Cells Arterioscler Thromb Vasc Biol, November 1, 2004; 24(11): 2075 - 2081. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Muscoli, I. Sacco, W. Alecce, E. Palma, R. Nistico, N. Costa, F. Clementi, D. Rotiroti, F. Romeo, D. Salvemini, et al. The Protective Effect of Superoxide Dismutase Mimetic M40401 on Balloon Injury-Related Neointima Formation: Role of the Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 J. Pharmacol. Exp. Ther., October 1, 2004; 311(1): 44 - 50. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Stocker and J. F. Keaney Jr. Role of Oxidative Modifications in Atherosclerosis Physiol Rev, October 1, 2004; 84(4): 1381 - 1478. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Liu, A. Ormsby, N. Oja-Tebbe, and P. J. Pagano Gene Transfer of NAD(P)H Oxidase Inhibitor to the Vascular Adventitia Attenuates Medial Smooth Muscle Hypertrophy Circ. Res., September 17, 2004; 95(6): 587 - 594. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Vittal, Z. E. Selvanayagam, Y. Sun, J. Hong, F. Liu, K.-V. Chin, and C. S. Yang Gene expression changes induced by green tea polyphenol (-)-epigallocatechin-3-gallate in human bronchial epithelial 21BES cells analyzed by DNA microarray Mol. Cancer Ther., September 1, 2004; 3(9): 1091 - 1099. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. M. Faraci and S. P. Didion Vascular Protection: Superoxide Dismutase Isoforms in the Vessel Wall Arterioscler Thromb Vasc Biol, August 1, 2004; 24(8): 1367 - 1373. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Cai, J. C. He, L. Zhu, M. Peppa, C. Lu, J. Uribarri, and H. Vlassara High Levels of Dietary Advanced Glycation End Products Transform Low-Density Lipoprotein Into a Potent Redox-Sensitive Mitogen-Activated Protein Kinase Stimulant in Diabetic Patients Circulation, July 20, 2004; 110(3): 285 - 291. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Adachi, D. R. Pimentel, T. Heibeck, X. Hou, Y. J. Lee, B. Jiang, Y. Ido, and R. A. Cohen S-Glutathiolation of Ras Mediates Redox-sensitive Signaling by Angiotensin II in Vascular Smooth Muscle Cells J. Biol. Chem., July 9, 2004; 279(28): 29857 - 29862. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. Stolen, G. G. Yegutkin, R. Kurkijarvi, P. Bono, K. Alitalo, and S. Jalkanen Origins of Serum Semicarbazide-Sensitive Amine Oxidase Circ. Res., July 9, 2004; 95(1): 50 - 57. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Young and J. W. Funder Eplerenone, But Not Steroid Withdrawal, Reverses Cardiac Fibrosis in Deoxycorticosterone/ Salt-Treated Rats Endocrinology, July 1, 2004; 145(7): 3153 - 3157. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Yoshimoto, N. Fukai, R. Sato, T. Sugiyama, N. Ozawa, M. Shichiri, and Y. Hirata Antioxidant Effect of Adrenomedullin on Angiotensin II-Induced Reactive Oxygen Species Generation in Vascular Smooth Muscle Cells Endocrinology, July 1, 2004; 145(7): 3331 - 3337. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Kusaka, G. Kusaka, C. Zhou, M. Ishikawa, A. Nanda, D. N. Granger, J. H. Zhang, and J. Tang Role of AT1 receptors and NAD(P)H oxidase in diabetes-aggravated ischemic brain injury Am J Physiol Heart Circ Physiol, June 1, 2004; 286(6): H2442 - H2451. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Jiang, S. Xu, X. Hou, D. R. Pimentel, and R. A. Cohen Angiotensin II Differentially Regulates Interleukin-1-{beta}-inducible NO Synthase (iNOS) and Vascular Cell Adhesion Molecule-1 (VCAM-1) Expression: ROLE OF p38 MAPK J. Biol. Chem., May 7, 2004; 279(19): 20363 - 20368. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K K Griendling Novel NAD(P)H oxidases in the cardiovascular system Heart, May 1, 2004; 90(5): 491 - 493. [Full Text] [PDF]
|
|
|
|
 |
|
 G. Ceolotto, M. Bevilacqua, I. Papparella, E. Baritono, L. Franco, C. Corvaja, M. Mazzoni, A. Semplicini, and A. Avogaro Insulin Generates Free Radicals by an NAD(P)H, Phosphatidylinositol 3'-Kinase-Dependent Mechanism in Human Skin Fibroblasts Ex Vivo Diabetes, May 1, 2004; 53(5): 1344 - 1351. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||