(Circulation. 1997;96:2361-2367.)
© 1997 American Heart Association, Inc.
Articles |
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
From the Zentrum der Physiologie, Klinikum der Johann Wolfgang Goethe Universität, Frankfurt am Main, Germany.
Correspondence to Takeshi Marumo, MD, PhD, Zentrum der Physiologie, Klinikum der Johann Wolfgang Goethe Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany. E-mail busse{at}merlin.add.uni-frankfurt.de
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionReferences |
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Background Platelet-derived growth factor (PDGF) and superoxide anion (O2·-) have been implicated in vascular diseases. We investigated whether PDGF stimulates the production of O2·- in human aortic smooth muscle cells (HSMCs) and whether O2·- leads in this way to the activation of nuclear factor–
B (NF-B) and induction of monocyte
chemoattractant protein 1 (MCP-1) in PDGF-stimulated HSMCs.
Methods and Results PDGF-AB concentration- and
time-dependently stimulated O2·- generation
from HSMCs. The stimulatory effect of PDGF-AB was mimicked by PDGF-BB
but not by PDGF-AA. The generation of O2·-
by PDGF-AB was attenuated by the NAD(P)H oxidase inhibitor
iodonium diphenyl, the specific protein kinase C (PKC)
inhibitor Ro 31-8220, and the phosphatidylinositol 3-kinase
inhibitor wortmannin. Allopurinol and
nifedipine had no effect on PDGF-AB–induced
O2·- release, whereas
indomethacin potentiated this response. Gel mobility
shift assay revealed that PDGF-AB increased the binding activity of
NF-B, which contained predominantly the p50/p65 heterodimer in
nuclear extracts from HSMCs. Superoxide dismutase as well as iodonium
diphenyl, Ro 31-8220, and wortmannin attenuated PDGF-AB–induced
activation of NF-B and expression of MCP-1 mRNA. In contrast,
superoxide dismutase did not inhibit the interleukin-1ß–induced
NF-B activation.
Conclusions The results demonstrate that PDGF
stimulates O2·- generation in HSMCs via
PKC-dependent and wortmannin-sensitive pathways involving
flavoenzyme(s). This PDGF-induced O2·-
production may be involved in vascular lesion formation by
mediating, at least in part, NF-B activation and MCP-1 induction.
Key Words: growth substances • atherosclerosis • lesion
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Platelet-derived growth factor plays an important role in intimal thickening after experimental angioplasty,1 2 and increased levels of PDGF have been shown in human atherosclerotic lesions,1 although its role in atherogenesis has not been clarified. PDGF activates the expression of a number of genes, including those encoding transcription factors, chemokines, and cytokines that participate in vascular lesion formation.3 Signal transduction pathways stimulated by PDGF include activation of phospholipase C
, PKC, PI3-kinase, mitogen-activated protein
kinase, and signal transducer and activator of
transcription proteins.4 Emerging evidence has pointed to the involvement of O2·- in the regulation of vascular functions. O2·- inactivates nitric oxide to yield peroxynitrite,5 6 stimulates the proliferation of VSMCs,7 and increases vascular tone.8 Studies using experimental animals have suggested that increased vascular O2·- production is associated with risk factors of atherosclerosis such as hypercholesterolemia,9 genetic hypertension,10 and diabetes.11 In hypertensive rats after chronic infusion of angiotensin II, the predominant source of increased O2·- generation is the vascular smooth muscle layer.12 Enzymatic sources involved in vascular O2·- production include xanthine oxidase, NAD(P)H oxidase, arachidonic acid–metabolizing enzymes, and NOS.13 14 15 16
Although both PDGF and O2·- have been
implicated in vascular diseases, it has not yet been demonstrated
whether PDGF can stimulate O2·-
production in VSMCs. In the present study, we examined the
effect of PDGF on O2·- production in
HSMCs. In addition, we investigated the potential role of
O2·- in the control of activation of NF-B
and induction of MCP-1 mRNA in PDGF-stimulated HSMCs.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Smooth Muscle Cell Culture
VSMCs isolated from the thoracic aorta of a young, healthy donor for cardiac transplantation by enzymatic disaggregation as described previously17 were kindly provided by Dr T. Scott-Burden (Texas Heart Institute, Houston). Cells were maintained in MEMTH, which consisted of MEM containing Earle's salts, 2 mmol/L glutamine, 5 mmol/L TES-NaOH, 5 mmol/L HEPES-NaOH (both pH 7.3), nonessential amino acids, 50 U/mL penicillin, and 50 µg/mL streptomycin, supplemented with 20% FCS. For experiments, cells at passages 16 through 20 were plated onto 12-well culture plates for measurements of O2·- release, 6-cm dishes for gel mobility shift assay, or 10-cm dishes for Northern blot analysis. After reaching confluence, cells were serum-deprived by 24-hour incubation with MEMTH supplemented with 0.1% BSA before all experiments.
O2·- Measurement
The release of O2·- was determined by
measuring SOD-inhibitable reduction of ferricytochrome c.
Cells were washed twice with HEPES-modified Tyrode's solution (pH 7.4)
and incubated in the same buffer with and without 500 U/mL SOD for 10
minutes at 37°C in humidified air. The composition of
HEPES-modified Tyrode's solution was as follows (in
mmol/L): CaCl2 1.8, KCl 2.6, MgCl2 0.49,
NaCl 137, NaH2PO4 0.36, glucose 5.6, and HEPES
10. In some experiments, HSMCs were pretreated with reagents for 15
minutes. Ferricytochrome c was added to the reaction buffer
solution to a final concentration of 81 µmol/L. HSMCs
were then stimulated with PDGF with or without reagents as indicated.
At the times indicated, the medium was removed, and the absorbance at
550 nm was measured immediately.
O2·--specific reduction of ferricytochrome
c was calculated from the difference in absorbance between
cells incubated with or without SOD by use of an extinction coefficient
of 2110 mm-1 ·
mol/L-1.18 After the
exposure of HSMCs to reagents that inhibited
O2·- release, >95% of cells were negative
with trypan blue.
Gel Mobility Shift Assay
HSMCs were washed twice with HEPES-modified Tyrode's solution
and exposed to agents as indicated. In some experiments, HSMCs were
pretreated with reagents for 15 minutes. Nuclear proteins were
extracted from HSMCs by the method of Schreiber et al19 as
described previously.20 Double-stranded
oligonucleotides containing the sequence of the binding
site for NF-B (5'-AGT TGA GGG GAC TTT CCC AGG C-3', Promega Corp)
were radiolabeled with 30 µCi [-32P]ATP with a 5'
end-labeling kit (Pharmacia Biotech GmbH). Nuclear proteins (6 µg)
were incubated with 3000 counts of labeled
oligonucleotide in (mmol/L) HEPES 10 (pH 7.5),
sodium chloride 100, EDTA 1, and dithiothreitol 1.5, with 5%
(vol/vol) glycerol and 2 µg poly(dI/dC) (Pharmacia Biotech
GmbH) for 30 minutes at room temperature. The reaction mixture was
loaded onto a native 6% polyacrylamide gel buffered with
(mmol/L) Tris 89, boric acid 89, and EDTA 2 and electrophoresed.
After vacuum drying, the gel was exposed to x-ray film at -70°C.
Densitometric analysis of the autoradiographic
results was performed after nonsaturating exposures. Values obtained
were normalized and expressed as percentages of control. In some
experiments, a supershift analysis was performed by
preincubation of nuclear extracts with 1 µg of a specific polyclonal
anti-p65 antibody or anti-p50 antibody for 12 hours at 4°C.
Northern Blot Analysis
HSMCs were incubated in MEMTH with 0.1% BSA with or without
agents as indicated for 4 hours. In some experiments, HSMCs were
pretreated with reagents for 15 minutes. Total RNA was extracted,
size-fractionated, and transferred to nylon membranes (Hybond,
Amersham-Buchler) as described previously.20 A 740-bp
Kpn I restriction fragment from the clone pXM-hJE34 (kindly
provided by Dr B.J. Rollins) containing the coding region for MCP-1/JE
and the cDNA probe specific for mouse 18S rRNA were labeled by the
random priming method with [
-32P]dCTP as previously
described.20 After hybridization with the probe and
washing, the blots were exposed to x-ray film at -70°C as described
previously.21
Reagents
Recombinant human PDGF-AB was purchased from R&D Systems Inc.
Recombinant human PDGF-AA and -BB were from Pepro Tech Inc. Recombinant
human IL-1ß was from CIBA-Geigy Co. Ro 31-8220 was from Roche
Products Ltd. Ferricytochrome c, wortmannin,
allopurinol, indomethacin, and
4,5-dihydroxy-1,3-benzene-disulfonic acid (Tiron) were from Sigma
Chemical Co. Iodonium diphenyl was from Fluka Chemie. SOD was from
Boehringer Mannheim GmbH. Polyclonal antibodies to p65 and p50
were from Santa Cruz Biotechnology Inc. FCS was from Biochrom KG. All
other chemicals and reagents were obtained from commercial sources and
were of reagent or molecular biology grade.
Stock solutions of PDGF were made in MEMTH with 0.1% BSA to a concentration of 10 µg/mL and stored at -20°C.
Statistics
Multiple comparisons were evaluated with ANOVA, followed by
Fisher's protected least significant difference method. Data are
presented as mean±SEM, and values of P<.05 were
considered statistically significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Effect of PDGF on O2·- Production
PDGF-AB concentration-dependently stimulated O2·- production in HSMCs as measured after a 1-hour incubation period (Fig 1A
). The generation of
O2·- by HSMCs increased within 20 minutes of
treatment and continued to increase for at least the next 40 minutes
(Fig 1B).
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) for increasing time intervals (B).
Superoxide production with vehicle at 1 hour (
) is also
shown in B. C, HSMCs were treated with vehicle, 100 ng/mL PDGF-AB (AB
100), 30 and 100 ng/mL PDGF-AA (AA 30 and AA 100), or 30 and 100 ng/mL
PDGF-BB (BB 30 and BB 100) for 1 hour. The values (mean±SEM) in A and
B are obtained from two separate experiments, and those in C are
representative of data obtained in one of two
qualitatively identical experiments with determinations performed in
triplicate. Symbol without bars indicates SEM within symbol.
*P<.05 vs control values. +P<.05 vs values at
20 minutes.
Significant release of O2·- was also
observed with PDGF-BB (30 and 100 ng/mL), whereas PDGF-AA (up to
100 ng/mL) failed to increase O2·-
production (Fig 1C
).
To elucidate the enzymatic source responsible for the PDGF-AB–induced
generation of O2·-, the effects of various
inhibitors were examined. Iodonium diphenyl (10
µmol/L), a potent inhibitor of flavoenzymes,
including NADPH oxidase,22 attenuated PDGF-AB–induced
O2·- production (Fig 2). In contrast, allopurinol (100
µmol/L), an inhibitor of xanthine oxidase, had no
effect (Fig 2). Surprisingly, indomethacin (10
µmol/L) significantly enhanced PDGF-stimulated
O2·- release, whereas the drug was
ineffective when applied alone (Fig 2).
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Next, the effects of various inhibitors of the signal
transduction pathway activated by PDGF in vascular cells on the
PDGF-stimulated O2·- release were examined.
Ro 31-8220 (1 µmol/L), a selective PKC
inhibitor,23 significantly inhibited
PDGF-AB–induced O2·- production
(Fig 3A). Wortmannin, a PI3-kinase
inhibitor that inhibits O2·-
release from neutrophils,24 significantly inhibited the
PDGF-AB–induced generation of O2·- at a
concentration of 0.1 µmol/L and completely abolished the
increase at 1 µmol/L (Fig 3B). Nifedipine
(0.1 and 1 µmol/L), a Ca2+ channel blocker
that has been shown to inhibit the PDGF-induced intracellular
Ca2+ elevation in VSMCs,25 did not
significantly modify the PDGF-AB–induced
O2·- generation (Fig 3C).
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Effect of PDGF-Stimulated O2·- Formation
on NF-B Activation
Because reactive oxygen intermediates have been shown to
activate NF-B,26 it was examined whether PDGF
activates NF-B in HSMCs via an increase in
O2·- generation. With the gel mobility shift
assay, at least two bands with specific NF-B binding activity were
detected in nuclear extracts from unstimulated HSMCs (Fig 4A). PDGF-AB significantly increased
NF-B binding activity at 30 and 60 minutes. The stimulatory effect
reached a peak within 30 minutes, then gradually decreased and returned
to the basal level at 120 minutes (Fig 4A). The induction of NF-B
binding activity by PDGF-AB was concentration dependent (Fig 4B).
Treatment of nuclear extracts with a specific anti-p65 antibody
resulted in a supershift of the slower but not the faster band in both
untreated and PDGF-treated cells, demonstrating the presence of p65 in
the slower but not the faster band (Fig 5). Addition of a specific anti-p50
antibody to nuclear extracts resulted in a supershift of both the
slower and the faster bands. These findings indicate that the
slower-migrating band represents the p50/p65 heterodimer and
the faster-migrating band contains the p50 subunit of NF-B.
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The role of O2·- generation in the
PDGF-AB–stimulated activation of NF-B in HSMCs was investigated
next. Incubation of HSMCs with SOD (500 U/mL) attenuated the
stimulatory effect of PDGF-AB (Fig 6A).
Tiron (10 mmol/L), another scavenger of
O2·-,15 also attenuated the
effect of PDGF-AB (Fig 6A). In addition, NF-B activation in response
to PDGF-AB was inhibited by iodonium diphenyl (50
µmol/L), Ro 31-8220 (1 µmol/L), and wortmannin
(1 µmol/L) (Fig 6B).
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We next investigated the effect of PDGF-AB on NF-B activation in
combination with IL-1ß, a potent activator of NF-B.
NF-B activation stimulated by 300 U/mL IL-1ß, a concentration that
elicited maximum NF-B binding activity in HSMCs, was significantly
augmented by PDGF-AB but was not affected by SOD (Fig 7).
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Effect of PDGF-Stimulated O2·- Formation
on MCP-1 mRNA Induction
Because the promoter of the human MCP-1 gene contains functionally
active NF-B binding sites,27 we tested whether
PDGF-induced expression of MCP-1 mRNA is decreased by inhibition of
O2·- production in HSMCs. PDGF-AB
induced a pronounced expression of MCP-1 mRNA within 4 hours, although
the basal level was barely detectable (Fig 8). This PDGF-induced MCP-1 mRNA
expression was inhibited by SOD, iodonium diphenyl, Ro 31-8220, and
wortmannin (Fig 8).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The present study shows that PDGF is a potent stimulant of O2·- generation in HSMCs. The finding that iodonium diphenyl inhibited this O2·- production implicates the involvement of flavoenzyme(s). Because NADH and NADPH oxidases have been shown to generate O2·- in VSMCs,14 15 it is conceivable that PDGF may activate these enzymes. An angiotensin II–induced increase in the activity of these oxidases in VSMCs has recently been shown.15 In this report, the increase in oxidase activity was observed only several hours after stimulation, suggesting the requirement of some induction steps for the activation of this enzyme system. In our study, however, a consistent and substantial production of O2·- was already evident within 20 minutes. Considering the time course required for the generation of O2·-, the pathways involved in oxidase activation in the present study may be different from those observed after stimulation with angiotensin II.
Earlier studies using nonrecombinant PDGF have shown that PDGF stimulates O2·- release from neutrophils and monocytes.28 29 However, a recent study has indicated that neutrophils do not respond to recombinant PDGF, suggesting that the production of O2·- observed in these previous studies might have been caused by contaminants copurified with PDGF.30 Thus, the stimulatory effect of PDGF on O2·- production in VSMCs seems to be a cell-type–specific phenomenon.
PDGF is a dimer of two polypeptide chains, A and B, forming three
isoforms, called PDGF-AA, PDGF-AB, and PDGF-BB.4 PDGF
isoforms bind and dimerize two PDGF receptors, and ß, with
different affinities. PDGF-A chain binds only the PDGF -receptor,
whereas the PDGF-B chain can bind either receptor. In the present
study, PDGF-AB and -BB but not -AA increased
O2·- production, suggesting that
PDGF exerts its effect via the ß-receptor.
The lack of inhibition by indomethacin of O2·- production suggests that arachidonic acid metabolism through cyclooxygenase does not seem to be a major source of O2·- in PDGF-stimulated HSMCs. Interestingly, indomethacin did further augment PDGF-stimulated O2·- production. Indomethacin has been shown to prevent cAMP elevation evoked by PDGF in VSMCs.31 Because cAMP elevation inhibited O2·- production in other cell types,13 it might be possible that the augmented release of O2·- induced by indomethacin is due to the inhibition of cAMP elevation.
PDGF stimulates phospholipase C, leading to the activation of
PKC,4 which in turn seems to be involved in
O2·- generation and the subsequent NF-B
activation and MCP-1 mRNA induction, because Ro 31-8220 inhibited these
responses. The increase in intracellular Ca2+
concentration, however, does not seem to play a major role in
O2·- generation in PDGF-stimulated HSMCs,
because nifedipine, which has been shown to inhibit
PDGF-stimulated elevation of intracellular Ca2+
concentration in VSMCs,25 had no effect on the
O2·- generation by PDGF.
Wortmannin inhibited O2·-
production, NF-B activation, and MCP-1 mRNA induction in
PDGF-stimulated HSMCs. However, the concentrations required (0.1 to
1 µmol/L) were higher than those reported to inhibit PI3
to kinase32 33 (IC50 values, 3 to 50
nmol/L) and O2·- release from
neutrophils24 (IC50 value, 7.3 nmol/L).
Wortmannin has also been reported to inhibit myosin light chain kinase,
a novel phosphatidylinositol 4–kinase and DNA-dependent protein kinase
at concentrations greater than those required to inhibit
PI3-kinase.32 33 Therefore, it is possible that wortmannin
exerted its inhibitory effect via a pathway other than the
inhibition of PI3-kinase in HSMCs.
The finding that PDGF activates NF-B in HSMCs is
consistent with recent data obtained in rat aortic smooth
muscle cells34 and murine NIH/3T3 cells.35
Our observations that all compounds that inhibited PDGF- induced
O2·- generation in HSMCs also attenuated the
activation of NF-B suggest a close link between
O2·- production and NF-B
activation. Moreover, the inhibitory effect of SOD and
Tiron on PDGF-induced NF-B activation further supports the notion
that O2·- generated in HSMCs acts as a
mediator for the activation of NF-B. This conclusion is
consistent with recent data showing that generation of
O2·- activates NF-B in mouse
mesangial cells.36 However, our finding that
SOD and Tiron did not completely inhibit the activation of NF-B in
response to PDGF suggests that other signal transduction pathways might
also be involved.
The IL-1ß–induced NF-B activation was augmented by PDGF in HSMCs.
Furthermore, activation of NF-B by IL-1ß was not inhibited by SOD,
and IL-1ß failed to increase O2·- release
from HSMCs (vehicle, 0.17±0.10 nmol · million
cells-1 · h-1
versus IL-1ß, 0.18±0.07 nmol · million
cells-1 · h-1,
n=6). These findings underline that PDGF activates NF-B
through a signaling pathway different from that activated by
IL-1ß. NF-B activation has been shown to be functionally important
in the induction of NOS type II.37 An
inhibitor of NF-B, pyrrolidine dithiocarbamate,
inhibited induction of NOS type II activity in vascular smooth muscle
layers.38 Despite its stimulatory effect on
IL-1ß–induced NF-B activation observed in the present study,
PDGF has been shown to inhibit the induction of NOS type II in response
to IL-1ß in VSMCs.17 Recently, transforming growth
factor-ß1 has been shown to inhibit NOS type II induction
in VSMCs by mechanisms distinct from inhibition of NF-B
activation.39 In conjunction with these findings, it is
conceivable that an as yet unknown inhibitory pathway on
induction of NOS type II might be switched on by PDGF that can overcome
the stimulatory drive of NF-B activation.
Treatments that inhibited PDGF-induced O2·-
production, as well as incubation with SOD, significantly
attenuated MCP-1 mRNA induction in response to PDGF. These changes were
associated with parallel changes in PDGF-induced NF-B activation,
supporting the hypothesis that PDGF-stimulated
O2·- production may be involved in
the activation of NF-B and subsequent induction of MCP-1 mRNA in
HSMCs. Recruitment of inflammatory cells to the
subendothelial space is one of the early events in
atherogenesis. MCP-1, which is secreted by
macrophage-derived foam cells and VSMCs in atherosclerotic
plaques,40 acts as a potent chemoattractant for
monocytes41 and T lymphocytes.42 Furthermore,
MCP-1 accounts for virtually all of the monocyte chemotactic activity
secreted by VSMCs exposed to minimally modified LDL.43
Increased MCP-1 mRNA is also observed in aorta after balloon
injury.44 Recent reports suggest the potential roles of
O2·- and NF-B in the development of
atherosclerosis and the arterial response
to injury. Increased vascular O2·-
production has been demonstrated in atherosclerotic animal
models,9 10 11 and coronary vasospasm after
experimental angioplasty is inhibited by SOD.45
Activated NF-B is present in human atherosclerotic
lesions,46 and administration of antisense
oligonucleotides to the p65 of NF-B inhibits
neointimal formation in balloon angioplasty–treated rat
carotid arteries.47 In conjunction with these reports, the
present study supports the idea that
O2·- generation and subsequent NF-B
activation in response to PDGF might contribute to vascular lesion
formation by stimulating the migration of vascular cells via induction
of MCP-1. It is tempting to explore the possibility that PDGF-induced
O2·- production might modulate the
expression of other NF-B–regulated molecules, such as
cytokines, adhesion molecules, colony-stimulating factors, and
tissue factor, which are implicated in atherogenesis and
restenosis after balloon angioplasty.46
Reduction of ferricytochrome c detects extracellular O2·- levels in the present study. It has been shown that O2·- generated intracellularly is capable of crossing the plasma membrane through anion channels48 and reacting in the extracellular space.49 Therefore, it is conceivable that O2·-, which we have measured, also reflects changes in intracellular O2·- levels. Although we cannot exclude the possibility that PDGF-stimulated HSMCs produce O2·- extracellularly like leukocytes,13 a partial equilibrium between extracellular and intracellular O2·- levels might exist through anion channels.
Considering that SOD cannot easily enter the cells because of its high
molecular weight, the findings that exogenous SOD blunted the
activation of NF-B and MCP-1 induction suggest that the
concentration of extracellular O2·-
modulates those intracellular responses in PDGF-treated HSMCs. In
agreement with our findings, extracellular generation of
O2·- has been shown to activate
NF-B36 and increase MCP-1 mRNA50 in mouse
mesangial cells. Extracellular
O2·- has been suggested to be at least
partly involved in other intracellular responses, including
intracellular alkalinization by phorbol ester in U937
cells,51 enhanced bradykinin-stimulated intracellular
Ca2+ elevation in vascular endothelial
cells by high glucose concentration,52 and inhibition of
cardiac muscle oxygen consumption by pyrogallol.53
Together with these reports, our findings support the concept that
alteration in extracellular O2·-
concentration could influence intracellular signaling pathways. Because
cytosolic oxidizing conditions appear to be important regulators of
NF-B activation,54 it is possible that the
intracellular redox state might change in parallel with extracellular
O2·- levels in PDGF-stimulated HSMCs.
However, the molecular target of O2·- and
the subsequent signaling pathways leading to NF-B activation remain
to be elucidated.
Hydrogen peroxide has been shown to be generated and to mediate signal
transduction pathways in PDGF-stimulated VSMCs.55 Because
hydrogen peroxide serves as a mediator of NF-B activation in some
cell types,54 it is possible that increased
O2·- might lead to NF-B activation, in
part via generation of intracellular hydrogen peroxide in PDGF-treated
HSMCs.
In conclusion, PDGF stimulates O2·-
generation in HSMCs via PKC-dependent and wortmannin-sensitive pathways
involving activation of flavoenzyme(s). This
O2·- generation, which represents a
novel biological activity of PDGF, is most likely to be involved in
NF-B activation and MCP-1 induction, which are important events in
the progression of atherosclerosis and
restenosis after balloon angioplasty.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by the Deutsche Forschungsgemeinschaft (Bu436/6-1). Dr Marumo is supported by the Uehara Memorial Foundation and Alexander von Humboldt-Stiftung. The authors are indebted to Dr Alexander Mülsch for many helpful discussions.
Received April 2, 1997; revision received May 8, 1997; accepted May 28, 1997.
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H. I. Krieger-Brauer, P. K. Medda, B. Sattel, and H. Kather Inhibitory Effect of Isoproterenol on NADPH-dependent H2O2 Generation in Human Adipocyte Plasma Membranes Is Mediated by beta gamma -Subunits Derived from Gs J. Biol. Chem., January 28, 2000; 275(4): 2486 - 2490. [Abstract] [Full Text] [PDF]
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W. Durante, K. J. Peyton, and A. I. Schafer Platelet-Derived Growth Factor Stimulates Heme Oxygenase-1 Gene Expression and Carbon Monoxide Production in Vascular Smooth Muscle Cells Arterioscler. Thromb. Vasc. Biol., November 1, 1999; 19(11): 2666 - 2672. [Abstract] [Full Text] [PDF]
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G. S. Hoare, N. Marczin, A. H. Chester, and M. H. Yacoub Role of oxidant stress in cytokine-induced activation of NF-kappa B in human aortic smooth muscle cells Am J Physiol Heart Circ Physiol, November 1, 1999; 277(5): H1975 - H1984. [Abstract] [Full Text] [PDF]
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H. Soejima, H. Ogawa, H. Yasue, K. Kaikita, K. Takazoe, K. Nishiyama, K. Misumi, S. Miyamoto, M. Yoshimura, K. Kugiyama, et al. Angiotensin-converting enzyme inhibition reduces monocyte chemoattractant protein-1 and tissue factor levels in patients with myocardial infarction J. Am. Coll. Cardiol., October 1, 1999; 34(4): 983 - 988. [Abstract] [Full Text] [PDF]
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M. M. Tarpey, C. R. White, E. Suarez, G. Richardson, R. Radi, and B. A. Freeman Chemiluminescent Detection of Oxidants in Vascular Tissue : Lucigenin But Not Coelenterazine Enhances Superoxide Formation Circ. Res., May 28, 1999; 84(10): 1203 - 1211. [Abstract] [Full Text] [PDF]
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X. Bao, C. Lu, and J. A. Frangos Temporal Gradient in Shear But Not Steady Shear Stress Induces PDGF-A and MCP-1 Expression in Endothelial Cells : Role of NO, NF{kappa}B, and egr-1 Arterioscler. Thromb. Vasc. Biol., April 1, 1999; 19(4): 996 - 1003. [Abstract] [Full Text] [PDF]
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T. Marumo, V. B. Schini-Kerth, R. P. Brandes, and R. Busse Glucocorticoids Inhibit Superoxide Anion Production and p22 Phox mRNA Expression in Human Aortic Smooth Muscle Cells Hypertension, December 1, 1998; 32(6): 1083 - 1088. [Abstract] [Full Text] [PDF]
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Q. Hu, G. Zheng, J. L. Zweier, S. Deshpande, K. Irani, and R. C. Ziegelstein NADPH Oxidase Activation Increases the Sensitivity of Intracellular Ca2+ Stores to Inositol 1,4,5-Trisphosphate in Human Endothelial Cells J. Biol. Chem., May 19, 2000; 275(21): 15749 - 15757. [Abstract] [Full Text] [PDF]
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W.-G. Li, F. J. Miller Jr., H. J. Zhang, D. R. Spitz, L. W. Oberley, and N. L. Weintraub H2O2-induced O-.2 Production by a Non-phagocytic NAD(P)H Oxidase Causes Oxidant Injury J. Biol. Chem., July 27, 2001; 276(31): 29251 - 29256. [Abstract] [Full Text] [PDF]
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S. S. Brar, T. P. Kennedy, A. B. Sturrock, T. P. Huecksteadt, M. T. Quinn, T. M. Murphy, P. Chitano, and J. R. Hoidal NADPH oxidase promotes NF-kappa B activation and proliferation in human airway smooth muscle Am J Physiol Lung Cell Mol Physiol, April 1, 2002; 282(4): L782 - L795. [Abstract] [Full Text] [PDF]
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F. J. Miller Jr, W. J. Sharp, X. Fang, L. W. Oberley, T. D. Oberley, and N. L. Weintraub Oxidative Stress in Human Abdominal Aortic Aneurysms: A Potential Mediator of Aneurysmal Remodeling Arterioscler. Thromb. Vasc. Biol., April 1, 2002; 22(4): 560 - 565. [Abstract] [Full Text] [PDF]
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