© 2001 American Heart Association, Inc.
Vascular Biology |
Increased NAD(P)H Oxidase and Reactive Oxygen Species in Coronary Arteries After Balloon Injury
From the Cardiovascular Research Center, Department of Medicine (Cardiology), Thomas Jefferson University, Philadelphia, Pa.
Correspondence to Yi Shi, MD, Thomas Jefferson University, Cardiovascular Research Center, Division of Cardiology, Suite 403D, 1025 Walnut St, Philadelphia, PA 19107. E-mail yi.shi{at}mail.tju.edu
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Abstract—Reactive oxygen species (ROS), produced by cellular constituents of the arterial wall, provide a signaling mechanism involved in vascular remodeling. Because adventitial fibroblasts are actively involved in coronary remodeling, we examined whether the changes in the redox state affect their phenotypic characteristics. To this end, superoxide anion production and NAD(P)H oxidase activity were measured in porcine coronary arteries in vivo, and the effect of ROS generation on adventitial fibroblast proliferation was examined in vitro. Superoxide production (SOD- and Tiron-inhibitable nitro blue tetrazolium [NBT] reduction) increased significantly within 24 hours after balloon-induced injury, with the product of NBT reduction present predominantly in adventitial fibroblasts. These changes were NAD(P)H oxidase–dependent, because diphenyleneiodonium (DPI) abolished superoxide generation (P<0.001). Furthermore, the injury-induced superoxide production was associated with augmented NAD(P)H oxidase activity and upregulation of p47phox and p67phox in adventitial fibroblasts (immunohistochemistry). Serum stimulation of isolated adventitial fibroblasts produced time-dependent increases in ROS production (peak 3 to 6 hours). The inhibition of ROS generation with NAD(P)H oxidase inhibitor (DPI) or the removal of ROS with antioxidants (Tiron, catalase) abrogated proliferation of adventitial fibroblasts. These results indicate that vascular NAD(P)H oxidase plays a central role in the upregulation of oxidative stress after coronary injury, providing pivotal growth signals for coronary fibroblasts.
Key Words: reactive oxygen species • NAD(P)H oxidase • coronary remodeling • adventitial fibroblast
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Introduction |
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Oxidative stress has been implicated in several steps leading to the development of vascular disease.1 2 Initial observations focused on reactive oxygen species (ROS) derived from invading macrophages and their possible involvement in oxidative lipid modifications in the vessel wall. Subsequently, it has become apparent that ROS are also produced in a controlled fashion by all vascular cells and that they act as "second messengers" regulating various cellular functions. Several extracellular signals, such as growth factors or even physical stimuli, induce ROS and their derivatives in vascular smooth muscle cells (SMCs) and fibroblasts, activating the intracellular growth program.3 4 5 6 For example, superoxide anion (·O2-) increases expression of extracellular signal–regulated kinase 1/2 mitogen-activated protein kinase, whereas H2O2 activates p38 mitogen-activated protein kinase and stress-activated proteins.7 8 Furthermore, H2O2 also stimulates early proto-oncogenes and redox-sensitive transcriptional factors (eg, NF-
B and
AP-1).9 In vascular cells, the major enzymatic source of intracellular ROS is NAD(P)H oxidase, which generates ·O2- by 1-electron reduction of molecular oxygen.10 11 12 Although NADPH oxidase is responsible for the burst of ·O2- in phagocytic cells, the generation of ROS in vascular cells differs from that in neutrophils. In the former, it occurs over a period of hours (rather than minutes), appears to be mostly intracellular (rather than extracellular and intracellular), and may involve the assembly of different enzymatic subunits of NAD(P)H oxidase.13 Significant progress has been made toward the identification of NAD(P)H oxidase subunits in normal vascular cells and in atherosclerotic lesions, including both membrane-associated (p22phox) and cytoplasmic (p67phox, p47phox, Rac1) components.6 14 15 16 The activity of the NAD(P)H oxidase in vascular cells is modulated by extracellular signals known to influence vascular remodeling and lesion development (eg, thrombin and angiotensin II).6 15 16 17 Furthermore, gene polymorphism affecting at least one of the subunits (p22phox) has been linked to the development of atherosclerosis in humans.18 19
The regulation of the redox state appears to be heterogeneous across the vessel wall. Higher expression of NAD(P)H oxidase and ·O2- production have been reported in normal adventitia than in the media.20 21 The importance of this finding initially remained unclear, because the activation of medial SMCs and lipid peroxidation occur in the proximity of the arterial lumen. Several studies from our laboratory and others, however, have suggested active involvement of adventitial fibroblasts in arterial repair.22 23 24 In particular, after severe coronary injury, these cells demonstrate preferential proliferation and migration toward intima. This is not surprising, because coronary SMCs display more advanced differentiation and a limited response to stimulation compared with noncoronary SMCs.25 26 In view of our previous findings and the established role of ROS in the regulation of cell proliferation, we hypothesized that the increase in oxidative stress after coronary injury involves adventitial fibroblasts. The results of this study demonstrated the upregulation of NAD(P)H oxidase activity and ROS production in adventitial fibroblasts after coronary injury. In cell culture, ROS are important signals for growth response of coronary fibroblasts. We postulate that phenotypic responsiveness of coronary fibroblasts to stimulation is mediated, in part, by NAD(P)H oxidase–derived oxidative stress.
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Methods |
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Animal Model
Domestic crossbred female pigs (12 to 15 kg) were anesthetized and instrumented as previously described.22 23 After the exposure of the right common carotid artery, heparin (5000 U) was administered intravenously. Coronary ostia were cannulated under fluoroscopic guidance, and intracoronary nitroglycerin was given (100 µg). Coronary injury was carried out in 2 coronary arteries in each animal with an oversized balloon (balloon:artery ratio
1.3 to 1.5) inflated
2 to 3 times for 30 seconds. The third artery was used as control. The
animals were euthanatized with intravenous Euthasol
(Delmarva Laboratory) at times indicated in the text. All experiments
were carried out in accordance with institutional
guidelines.
Measurement of
·O2-
Production
The production of
·O2- was measured
by superoxide dismutase (SOD)– or Tiron-inhibitable conversion of
nitro blue tetrazolium (NBT) to
formazan.20 21
·O2-
Production in Coronary Arteries
Coronary arteries were dissected free from
adipose tissue and myocardium, then cut into 5-mm rings
and placed in 24-well plates. Tissues were balanced in phenol-free DMEM
at 37°C in a CO2 incubator for 30 minutes with
or without addition of
·O2- SOD (1000
U/mL) or Tiron (10 mmol/L). Freshly made NBT (100 mg/L in
phenol-free DMEM) was added to tissues with gentle rocking for 3 hours.
The reaction was terminated by addition of an equal volume of 0.5N HCl,
and tissues were rinsed twice with cold PBS. To extract formazan,
tissues were pulverized in liquid nitrogen and dissolved in 100%
pyridine at 80°C for 30 minutes. After
centrifugation, light absorbance was read in
supernatants at 540 nm. The NBT reduction to formazan was calculated by
the following formula: NBT reduction=AxV/(TxExL), where A is
absorbance, V is volume of solubilizing solution, T is time of
incubation with NBT (minutes), E is extinction coefficient=0.72
mmol/mm, and L is length of light travel through the solution,
10 mm. Either SOD- or Tiron-inhibitable NBT reduction was
calculated as a measure of
·O2-
production (pmol · min-1 · mg
wet wt-1). To determine pathways mediating
·O2-
production, several inhibitors were used in the
experiments, including diphenyleneiodonium (DPI, 100 µmol/L),
rotenone (50 µmol/L), oxypurinol (300 µmol/L),
N
-nitro-L-arginine
methyl ester (L-NAME, 1 mmol/L), and diethyldithiocarbamic acid
(10 mmol/L). The n value represents the number of vascular
rings obtained from 
3 animals per experimental condition.
To assess the location of injury-induced ·O2- production, the injured coronary arteries were incubated with NBT and processed to visualize formazan deposits. Briefly, coronary rings were fixed in 10% formalin and embedded in paraffin. They were sectioned into 6-µm-thick sections and deparaffinized by heating at 65°C for 1 hour. To avoid solubilization of NBT in tissue, the sections were rinsed with Clear-Rite 3 solution (Richard-Allan Scientific) and counterstained with nuclear fast red.
·O2-
Production in Isolated Adventitial Fibroblasts
Adventitial fibroblasts (passages 2 through 6) were
plated in 6-well plates at 100 000 cells/well in 10% FBS. At 2 days
later, when cells were 80% confluent, they were arrested in 0.5%
FBS for the next 48 hours. After that, they were stimulated with 10%
FBS for 1 to 24 hours, followed by incubation with NBT (0.5 mg/mL in
phenol-free DMEM) for 1 hour. After brief washing, cells were
trypsinized and cell pellets were dissolved in 100% pyridine. The
light absorbance was measured at 540 nm and the NBT reduction to
formazan was calculated as described above and corrected by cell
number. Values were derived from 6 to 9 wells from 3 separate
experiments.
Measurement of NAD(P)H Oxidase Activity in
Coronary Arteries
NAD(P)H oxidase activity was measured by
SOD-inhibitable cytochrome c
reduction using NADH or NADPH as
substrate.17 To measure
NAD(P)H oxidase activity in injured coronary arteries, the
arteries were harvested at 2 days after injury, and the injured
segments (including the adventitia and media) were dissected free from
adipose tissue and myocardium. The noninstrumented
coronary arteries were used as control. After the removal of
endothelial cells, tissues were minced in 10 volumes of
ice-cold Tris-sucrose buffer (pH 7.1) containing Tris base 10
mmol/L, sucrose 340 mmol/L, PMSF 1 mmol/L, EDTA 1
mmol/L, leupeptin 10 µg/mL, aprotinin 10 µg/mL, and pepstatin 10
µg/mL. Then the tissue homogenates were sonicated for 20
seconds on ice, followed by extraction for 30 minutes. After
centrifugation at
15 000g for 10 minutes, an
aliquot (20 µL) of supernatant (50 to 150 µg of protein) was added
to the reaction buffer (980 µL) containing cytochrome
c (78 µmol/L), NADH, or NADPH
(100 µmol/L), with or without SOD (1000 U/mL). The samples were then
incubated at 37°C for 1 hour, and the absorbance at 550 nm was
measured. There was no measurable activity in absence of NADH. A buffer
blank was measured in each assay, and SOD-inhibitable cytochrome
c reduction in buffer blank was
subtracted from each sample. The activity of NAD(P)H oxidase was
calculated as SOD-inhibitable cytochrome
c reduction and expressed as
·O2- in pmol ·
mg-1 ·
min-1.
Measurement of SOD Activity in
Coronary Arteries
SOD activity in vascular tissues was measured by
SOD-dependent inhibition of cytochrome
c reduction catalyzed by
xanthine/xanthine oxidase.27
To assess SOD activity in uninjured coronary arteries,
coronary adventitia and media were dissected after the removal
of endothelium. SOD activity after coronary
injury was measured in arterial segments including the
adventitia and media. The tissues were minced and
homogenized in 10 volumes of 50 mmol/L potassium
phosphate (pH 7.4) containing 0.3 mol/L KBr and a cocktail of protease
inhibitors (0.5 mmol/L PMSF, 90 µg/mL aprotinin, 10
µg/mL pepstatin, 10 µg/mL leupeptin). After sonication for 20
seconds, the homogenates were extracted at 4°C for 30
minutes, followed by centrifugation at
15 000g for 10 minutes. The
supernatants were added to the reaction mixture consisting of 0.1
mmol/L EDTA, 0.090 mmol/L xanthine, and 0.018 mmol/L
cytochrome c (pH 7.4). SOD
activity was assessed by monitoring the inhibition of xanthine
oxidase–mediated cytochrome c
reduction, with the absorbance measured at 550 nm over 3
minutes.
Immunohistochemistry
The Vectastain Elite ABC system (Vector Laboratories)
was used for immunohistochemistry as previously
described.22 28
Sections were deparaffinized, incubated with 0.6%
H2O2 in methanol for 30
minutes, and blocked with 5% horse or rabbit serum. After being washed
in PBS, sections were incubated with primary antibodies for 1 hour at
room temperature in a moisture chamber. The following primary
antibodies were used: polyclonal antibodies against
p47phox and
p67phox (1:200, Santa Cruz), monoclonal
antibody recognizing SM myosin heavy chain (SM-MHC, 1:800, Sigma), and
porcine macrophages (1:10, ATCC HB 142). Then slides were
washed and incubated with biotinylated secondary horse anti-mouse or
rabbit anti-goat antibodies (1:2000, Vector Laboratories) for 1 hour.
They were visualized with DAB substrate (Vector Laboratories) followed
by counterstain with Gill’s hematoxylin (Sigma
Diagnostics). Negative controls were carried out with
nonimmune serum instead of primary antibody.
Cell Proliferation Assay
Fibroblasts were isolated from the adventitia of
porcine coronary arteries as
described.26 The cells
(passages 2 to 6) were plated in triplicate at 10 000 cells/well in
24-well plates in DMEM supplemented with 10% FBS. At 24 hours later,
cells were arrested in DMEM containing 0.5% FBS for 48 hours. They
were then stimulated with 10% FBS for 3 days with or without addition
of indicated inhibitors. Cells were trypsinized at 72 hours
after stimulation and counted in a Coulter counter. Values were derived
from 3 wells per treatment, and the experiments were repeated 3 times
on separate occasions.
Statistical Analyses
Data were expressed as mean±SD. The
statistical significance regarding multigroup comparisons was
determined by ANOVA with Bonferroni correction. A value of
P<0.05 was considered
significant.
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Results |
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Oxidative Stress in Normal and Injured Coronary Arteries
Normal Coronary Arteries
Normal coronary adventitia exhibited higher basal ·O2- generation (4.4±1.2 pmol · mg-1 · min-1 SOD-inhibitable NBT reduction) than did the media (0.4±0.5 pmol · mg-1 · min-1, n=6, P<0.01). As shown in Figure 1
, the preincubation of coronary rings with
DPI [NAD(P)H oxidase inhibitor] abolished
·O2-
production in coronary adventitia, whereas rotenone
(mitochondrial dehydrogenase inhibitor) and oxypurinol
(xanthine oxidase inhibitor) had no effect. The difference
in basal ·O2-
generation between coronary adventitia and media is probably
due to heterogeneous distribution of endogenous
SOD, inasmuch as adventitia exhibited lower SOD activity than did media
(101±7 versus 166±9 U/g,
P<0.001, n=5). Subsequently,
SOD inhibitor (diethyldithiocarbamic acid) augmented more
·O2- generation
in the media (adventitia 19.6±2.5 and media 36.3±8.2
pmol · mg-1 · min-1,
P<0.01 versus no
diethyldithiocarbamic acid).
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P<0.001 vs coronary adventitia without treatment (n=6 to 9 vascular rings per bar).
Injured Coronary Arteries
Because coronary injury induces a short-lived
adventitial cell proliferation, the change in oxidative stress during
this time period was examined. To this end, the SOD activity and
·O2- generation
were measured in the entire coronary segments, because precise
separation of the adventitia from media is not technically feasible at
early time points after injury. SOD activity showed no difference
between control and injured coronary segments (not shown).
·O2- generation,
as measured by SOD- and Tiron-inhibitable NBT reduction, increased
significantly within 1 day after injury, and it remained elevated for
10 days
(Figure 2). Higher values of Tiron-inhibitable NBT reduction
were probably due to better cellular permeability of Tiron than SOD. To
ascertain the site of
·O2- generation
in injured vessels, reduced NBT (formazan) was identified in cross
sections.
Figure 3 demonstrates preferential adventitial localization
of intracellular deposits of formazan in injured segments. As in
uninjured vessels, NAD(P)H oxidase inhibitor (DPI) almost
entirely abolished the production of
·O2- after
coronary injury (n=4 per time point,
P<0.001 versus no treatment).
Although dynamic changes in inducible nitric oxide synthase expression
during coronary repair could contribute to oxidative stress,
its inhibitor, L-NAME, showed no effect
(Table 1).
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NAD(P)H Oxidase Activity and Expression of
Subunits
NAD(P)H Oxidase Activity
To ascertain that NAD(P)H oxidase is the major pathway
responsible for oxidative stress after coronary injury,
NADH/NADPH oxidase activity was measured by SOD-inhibitable cytochrome
c reduction using NADH or NADPH
as substrates. At baseline, coronary arteries exhibited similar
levels of NADH and NADPH oxidase activity. At 2 days after
coronary injury, NADH oxidase activity was significantly
augmented in the injured and adjacent segments
(Table 2), whereas NADPH oxidase activity showed no changes
after coronary injury.
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Expression of
p47phox and
p67phox
To localize NAD(P)H oxidase in injured coronary
arteries, expression of p47phox and
p67phox [cytoplasmic subunits of NAD(P)H
oxidase] were examined by immunohistochemistry. They were low in
normal coronary arteries (not shown) but showed a marked
increase in adventitial cells after injury. The expression began at 1
day and peaked at 2 days after injury. Positive cells were of
fibroblastic origin, because they lacked SM differentiation markers
(SM-MHC, 
-SM actin, desmin, and caldesmon), and only infrequent
cells (<5%) were positive for macrophage immunoreactivity
(Figure 4).
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Role of NAD(P)H Oxidase–Derived ROS
Production in Coronary Fibroblast Proliferation
Serum-Induced Superoxide Production
in Adventitial Fibroblasts
To assess the functional importance of increased
oxidative stress in coronary adventitia, the
·O2-
production was examined in serum-stimulated adventitial
fibroblasts. In response to serum stimulation, adventitial fibroblasts
demonstrated a time-dependent increase in
·O2-
production, reaching maximum levels at 3 to 6 hours
(Figure 5). As expected, either the inhibition of NAD(P)H
oxidase with DPI (10 µmol/L) or dismutation of
·O2- with
exogenous SOD (500 U/mL) produced significant reduction in
·O2-
production
(Figure 6), whereas L-NAME, rotenone, and oxypurinol showed
no effects (not shown).
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Serum-Induced Superoxide Generation and
Adventitial Fibroblast Proliferation
To assess whether altering ROS generation could
modulate adventitial fibroblast proliferation in vitro, growth
inhibition of serum-stimulated cells was determined either by
inhibiting the generation of ROS (DPI) or facilitating their
removal (·O2-:
Tiron, SOD; and H2O2:
catalase). The inhibitor of NAD(P)H oxidase (DPI)
significantly inhibited fibroblast growth in a concentration-dependent
manner
(Figure 7, P<0.001). In contrast, L-NAME
and oxypurinol produced no significant effects (not shown),
consistent with the lack of inhibition of ROS generation by
these inhibitors. The removal of either
·O2- with Tiron
or H2O2 with catalase
inhibited fibroblast proliferation. In contrast, dismutation of
·O2- to
H2O2 after SOD did not
prevent serum-induced cell
replication.
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The major findings of this study were that (1) coronary adventitia is an important source of increased oxidative stress after endoluminal coronary injury, (2) the NAD(P)H oxidase is the major pathway for ROS generation in injured coronary arteries and stimulated adventitial fibroblasts, and (3) ROS are involved in the regulation of growth response of coronary adventitial fibroblasts.
Oxidative stress is known to increase after various forms of
vascular
insult.6 29 30
Although the presence of NAD(P)H oxidase has been shown in normal
adventitia,16 20 21
its role in cellular proliferation during arterial repair
has not previously been elucidated. In noncoronary vasculature,
there is a rapid decrease in glutathione level, an indirect marker of
the redox state, after mechanical
injury.30 Others have
reported the induction of p47phox, thus
implicating NAD(P)H oxidase and ROS generation in initial SMC
proliferation.6 Likewise,
p22phox expression and oxidative stress are
increased in aortic medial SMCs after angiotensin II
infusion.31 Unique
characteristics of coronary SMCs, however, raise the question
of whether similar events occur during coronary
repair.25 26
Earlier studies showed an increase in
·O2-
production at 2 weeks after coronary injury, although
the presence of the neointima, containing cells of
adventitial and medial origin, blood-borne cells, and regenerating
endothelial cells, did not allow for the identification
of its source.29 To
characterize the mechanism of oxidative stress and its role in cellular
proliferation, the present study focused on earlier stages of
coronary response to injury, with cellular constituents still
remaining at their sites of origin. Predominant increases in ROS
generation and vascular NAD(P)H oxidase
(p47phox and
p67phox subunits) were evident in the
adventitia
(Figures 3
and 4). In contrast, coronary media
exhibited higher levels of SOD and subsequently lower oxidative stress.
It remains to be determined whether the degree of SMC differentiation,
which differs among vascular beds, contributes to regional differences
in the activation of NAD(P)H oxidase and ROS generation after injury.
The inhibition of NAD(P)H oxidase with DPI or the removal of ROS
(·O2- and
H2O2 with Tiron or
H2O2 with catalase)
abrogated serum-induced growth response of isolated coronary
fibroblasts in vitro
(Figure 7). Not surprisingly, dismutation of
·O2- to
H2O2 after SOD was
ineffective in preventing cell replication, pointing to the essential
role of H2O2 in the
regulation of vascular cell
growth.3 The above findings
suggested the involvement of ROS in a rapid proliferation of
adventitial fibroblasts after coronary injury in
vivo.22 23 24
The relatively slow and prolonged ROS production in adventitial
fibroblasts
(Figure 5) was similar to that in noncoronary SMCs
but quite distinct from the faster and greater response previously seen
in phagocytes.32
Preferential utilization of NADH as substrate for NAD(P)H oxidase in
injured coronary arteries contrasts with the observations by
others that aortic adventitial fibroblasts primarily generate
·O2- in response
to NADPH.12 21
Several experimental conditions (eg, cell origin and type of
stimulation), as well as assay methods (eg, cytochrome
c reduction versus lucigenin
assay) may be responsible for these
differences.33
The increase in oxidative stress stimulates cell growth, but ROS can also cause cellular death (reviewed by Griendling and Harrison).34 It is likely that these opposite results are related to the level and the type of ROS (·O2- versus H2O2).35 36 Much less is known, however, regarding the consequences of oxidative stress in vascular cells with a broad range of differentiation. When terminally differentiated cardiomyocytes and interstitial fibroblasts were exposed to H2O2, apoptosis was induced in the former and proliferation in the latter.37 Although endoluminal injury in a porcine model did not significantly enhance intracellular ROS generation in coronary media, extracellular oxidative stress may impact SMC survival. In chronic intimal lesions, inflammatory cells, particularly active in the generation of oxidative stress, have been shown to contribute to SMC apoptosis.38 The loss of differentiated coronary SMCs may lead to a decrease of a protective barrier of the intact media, resulting in the expansion of less differentiated fibroblasts and the development of intimal lesions. Our results support the notion that ROS production may serve as an attractive target for therapeutic interventions. Nevertheless, several questions remain unresolved, including the choice of antioxidants, because negative clinical results with vitamin E.39 In contrast, 2 independent clinical studies suggested a reduction in coronary restenosis in patients pretreated with the antioxidant probucol before angioplasty.40 41 The recently published Heart Outcomes Prevention Evaluation (HOPE) trial also provided evidence for the reduction of cardiovascular mortality after chronic administration of the ACE inhibitor ramipril.42 These results are particularly notable because NAD(P)H oxidase activity is regulated by angiotensin II.10 15 21 Undoubtedly, better understanding of the regulation of NAD(P)H oxidase in different vascular cells may provide further insights into the pathogenesis of coronary artery disease and aid the development of therapeutic interventions.
In conclusion, this study demonstrated an increase in NAD(P)H oxidase–derived ·O2- production in coronary adventitial fibroblasts after balloon injury. The inhibition of NAD(P)H oxidase and the attenuation of ROS production abrogated proliferative responses of adventitial fibroblasts. The results imply that ROS serve as pivotal signals for growth response of coronary fibroblasts.
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Acknowledgments |
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This study was supported by National Institutes of Health grants HL-44150 and HL-60672.
Received December 4, 2000; accepted January 8, 2001.
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