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Hypertension and Vascular Research Division, Henry Ford Hospital, Detroit, Michigan 48202-2689
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Although NAD(P)H oxidase-derived superoxide
(O2
) is increased during the development of
angiotensin II (ANG II)-dependent hypertension, vascular regulation at
the protein level has not been reported. We have shown that four major
components of NAD(P)H oxidase are located primarily in the vascular
adventitia as a primary source of vascular O2. Here
we compare vascular levels of O2 and NAD(P)H oxidase
in normotensive and ANG II-infused hypertensive mice and show that,
after 7 days of ANG II infusion (750 µg · kg1 · day1 ip) in
C57B1/6 mice, systolic blood pressure was increased compared with that
after sham infusion, concomitant with increased O2 in
the thoracic aorta as measured using lucigenin (25 µM)-enhanced chemiluminescence. Both p67phox and
gp91phox were detectable by Western blotting in
aortic homogenates, and we observed increased protein levels of
NAD(P)H oxidase subunits. These ANG II-induced increases were
normalized by simultaneous treatment with the AT1
receptor antagonist losartan. Moreover, the primary location of these
subunits was the adventitia as detected immunohistochemically. Our
results suggest that ANG II-induced increases in O2
are due to increased adventitial NAD(P)H oxidase activity, brought about by the heightened expression and interaction of its components.
hypertension; superoxide anion; free radicals; reactive oxygen species; NAD(P)H oxidase; NAD(P)H oxidoreductase
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THE CAPACITY OF SUPEROXIDE
ANION (O2) to impair nitric oxide
(NO)-dependent vasodilatation (12, 28, 31) and enhance endothelium-dependent constriction (16, 39) has been
extensively demonstrated in vitro, and several studies have shown that
O2 is involved in the development of hypertension.
Superoxide dismutase (SOD) was shown to lower blood pressure in
spontaneously hypertensive rats (SHR) (30). In rats with
acute angiotensin II (ANG II)-induced hypertension, SOD and catalase
inhibited vascular hyperpermeability and cellular damage related to the
hypertension (44), suggesting the involvement of
O2 and hydrogen peroxide, respectively. In ANG II
models of hypertension in rats and SHR, endothelium-dependent
relaxations were impaired (6, 25) and
endothelium-dependent contractions were enhanced (23).
Moreover, treatment of SHR with angiotensin-converting enzyme
inhibitors in vivo normalized aberrant ex vivo aortic relaxations and
contractions (6, 25). Recent reports have shown that ANG
II can stimulate O2 in phagocytes, aortic smooth
muscle cells, and adventitial fibroblasts via NAD(P)H oxidases
(11, 18, 34), implicating ANG II-induced O2 in these two forms of hypertension.
In the rat aorta, further studies have corroborated our finding that
the adventitia is a major site of vascular O2
production and NAD(P)H oxidase component expression under basal conditions (34) and have demonstrated the involvement of
adventitial O2 in the destruction of
endothelium-derived NO and the development of passive tone during ANG
II-dependent hypertension (42, 43). Because of the
potential importance of the adventitia in the regulation of NO function
and vascular physiology (46), we have focused our studies
on aortic adventitial NAD(P)H oxidase in mice to study its regulation
in various knockout and transgenic models. The purpose of this study
was to examine the location and expression of NAD(P)H oxidase
components in the mouse aorta and to investigate whether protein levels
are increased by ANG II.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Materials. Lucigenin and diethyldithiocarbamate (DDC) were solubilized in physiological buffer; 4,5-dihydroxy-1,3-benzene disulfonic acid (Tiron) was solubilized in H2O. These compounds were purchased from Sigma (St. Louis, MO). Diphenylene iodonium was purchased from Biomol (Plymouth Meeting, PA) and solubilized in dimethyl sulfoxide, losartan was obtained from Merck (Whitehouse Station, NJ) and diluted in drinking water, and ANG II was obtained from Sigma and diluted in 0.9% saline with 0.01 N acetic acid. Monoclonal and polyclonal antibodies against gp91phox and p67phox (4, 7) were generously supplied by Dr. Mark Quinn (Montana State University, Bozeman, MT).
Animals and systolic blood pressure measurements. C57Bl/6 male mice, 8-9 wk old, were purchased from Taconic Farms. They were kept in the animal facility for 1 wk before surgery was performed, and blood pressure was measured daily for training and adjustment to the technique (see Surgery). Systolic blood pressure was measured on days 0 (basal), 3, 5, and 7 after surgery in awake mice with the use of a noninvasive computerized tail-cuff system (BP-2000; Visitech, Apex, NC). Mice were placed in temperature-controlled chambers (37°C), and blood pressure was recorded in 3 cycles of 10 measurements. Cycles with standard deviations >20 were discarded.
Surgery.
All protocols using live animals were approved by the Henry Ford
Hospital Committee for the Care and Use of Experimental Animals. Alzet
mini-osmotic pumps (Alza Pharmaceutics, Palo Alto, CA) containing either vehicle (0.01 N acetic acid in saline solution) or ANG II
(0.75 mg · kg1 · day1 for 7 days) were implanted intraperitoneally under sterile conditions. Some
of the animals in the ANG II group were given losartan (30 mg · kg1 · day1) in
drinking water. Seven days after surgery was performed, animals were
killed and the thoracic and abdominal aorta were removed.
O2 production.
O2 production was measured by lucigenin-enhanced
chemiluminescence (ECL) assay as described previously (34,
36), except that the lucigenin concentration was decreased from
250 to 25 µM to avoid the artifactual O2 described
by Liochev and Fridovich (24), a concentration that was
validated by Li et al. (21). Thoracic aortic rings
(0.5 cm) were cleaned and incubated for 30 min in modified Krebs-HEPES buffer of the following composition (in mM): 119 NaCl, 20 HEPES, 4.6 KCl, 1.0 MgSO4, 0.15 Na2HPO4, 0.4 KH2PO4, 5 NaHCO3, 1.2 CaCl2, and 5.5 glucose (pH 7.4) at 37°C in the presence
of either 10 mM DDC alone or 10 mM DDC plus 0.1 mM diphenylene
iodonium, a flavoprotein inhibitor of NAD(P)H oxidases. Rings were
transferred to small plastic tubes containing 25 µM lucigenin in
modified Krebs-HEPES buffer and incubated for 10 min at 37°C in the
dark. After incubation, tubes were placed in a luminometer (TD-20e; Turner Designs, Sunnyvale, CA). Luminescence measurements were integrated for 30-s periods, and the cycle was repeated 9 times; the 10 values were then averaged. After 10 cycles, the cell-permeant O2 scavenger Tiron (10 mM) was added, and 15 more
cycles were read; the final 8 values, which appeared to be maximally
reduced, were averaged. Data were calculated as the change in
the rate of luminescence per minute per milligram of tissue of values
before and after Tiron and then converted to O2
(nmol · min1 · mg tissue1)
as described previously (34).
Immunoblotting.
Abdominal aortas were cleaned and homogenized in a glass-on-glass
homogenizer in 10 mM Tris · HCl (pH 7.5), 100 mM NaCl, 300 mM
sucrose, 1 mM EDTA, 0.2 mM phenylmethylsulfonyl fluoride, and 0.01 mg/ml each of leupeptin, aprotinin, and pepstatin. Fresh protease
inhibitors were added at the time of homogenization. Samples were
either used immediately or stored at 
70°C. Homogenates were run on
10-20% gradient gels (Owl Separation Systems), transferred to
nitrocellulose membranes (Amersham), and blotted with a previously characterized monoclonal antibody (1:1,000 dilution) against
gp91phox (4) and monoclonal and
polyclonal antibodies (1:1,000) against p67phox
(7); the secondary antibody was goat anti-mouse IgG
(Fab-specific, Sigma) for the monoclonal antibodies or goat anti-rabbit
(Amersham) for the polyclonal antibodies. Blots were developed using
ECL reagent (Amersham). Band intensity was compared by using an
automated densitometer (model GS-670; Bio-Rad).
Immunohistochemistry. To prepare aortas for immunohistochemistry, we anesthetized C57Bl/6 mice, opened the thoracic cavity, and then performed perfusion transcardially by heart puncture, first with PBS and then with Formalin. Thoracic aortas were embedded in paraffin. Sections were then treated with cold acetic acid for 10 min, air-dried, washed with PBS, and blocked with 1% goat serum in PBS for 30 min at room temperature. They were incubated overnight with the same monoclonal antibodies against gp91phox and p67phox (1:500 dilution) used for Western blot analysis or with IgG 2a and IgG 1 isotype controls in PBS. After being washed with PBS, the sections were incubated in the dark for 45 min at room temperature with Fluorolink Cy3-labeled goat anti-mouse antibody (Amersham) diluted 100 times in PBS. Sections were washed with PBS, mounted, and examined by fluorescence microscopy.
Statistical analysis.
Data are expressed as means ± SE, and n represents the
number of animals used for each experiment performed on separate days. The significance of point differences in O2
generation was determined by a one-way ANOVA, and mean blood pressure
was determined by ANOVA with repeated measures. Because of the large
variability, Wilcoxon's nonparametric test was used when the effect of
ANG II on p67phox and
gp91phox expression was analyzed.
P < 0.05 was considered statistically different.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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O2 generation in mouse thoracic aortas.
ANG II infusion caused significant elevation of systolic blood
pressure, and this increase was completely inhibited by the addition of
losartan to the drinking water (Fig. 1).
On day 7 we observed a significant increase in aortic
O2 production in ANG II-treated mice that was
inhibited by coadministration of losartan, an AT1 receptor
antagonist (Fig. 2). Treatment of rings
with diphenylene iodonium (100 µM) reduced ANG II-induced O2 to levels not statistically different from those
in sham treatment (not shown, n = 5). These data were
collected from rings equilibrated in the presence of 10 mM DDC to
inhibit Cu,Zn SOD (36). In recent experiments with rings
not treated with DDC, there was a 385 ± 89% increase in
O2 levels (n = 3, P < 0.05).
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Western blot expression of gp91phox and
p67phox.
We tested whether the infusion of ANG II would increase expression of
NAD(P)H oxidase components in mouse aortas. Western blots of aortic
homogenates from vehicle-infused mice treated with monoclonal antibody
against human gp91phox exhibited a
cross-reactive band of ~77 kDa (Fig.
3A), a value less than that
reported for human gp91phox but higher than that
expressed from the mouse phagocyte gp91phox
clone (2); these discrepancies are likely related to
varying degrees of glycosylation (2). The intensity of
this band was increased in homogenates from ANG II-infused mice,
whereas with ANG II plus losartan-treated mice, the intensity was not
different from that in sham treatment (Fig. 3, A and
B, n = 11). Membranes exposed to the
monoclonal or polyclonal antibody to p67phox
demonstrated cross-reactivity at ~67 kDa, a value that was enhanced in homogenates from ANG II-treated mice and not different from sham-treated mice given ANG II plus losartan (Fig.
4).
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Localization of NAD(P)H oxidase in control mouse aortas.
We have previously documented NAD(P)H oxidase in the adventitia of both
rabbit and rat blood vessels (34, 43). Using the same
antibodies and similar techniques, we localized two components of
NAD(P)H oxidase, p67phox and
gp91phox, to the aortic adventitia of C57Bl/6
mice. Figure 5 shows fixed cross sections
of mouse aorta exposed to monoclonal antibodies against
p67phox (Fig. 5A) and
gp91phox (Fig. 5B), followed by
incubation with a fluorescence-tagged secondary antibody. Control
isotype IgG did not show cross-reactivity (not shown).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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These are the first studies to our knowledge showing that ANG II
increases aortic protein levels of NAD(P)H oxidase components concomitant with increased O2 production and
elevations in blood pressure, and they strongly suggest that NAD(P)H
oxidase can be regulated at the protein level. These data support
previous findings in rats and rabbits showing that ANG II stimulates
vascular tissue to produce NAD(P)H oxidase-derived O2
(11, 42) while corroborating our previous findings that
the adventitia is the major site of vascular NAD(P)H oxidase (34, 42, 43).
A variety of studies have documented induction of vascular
O2 production by ANG II and characterized the source
as NAD(P)H oxidase (11, 14, 34, 38). The data reported
here extend those findings to the mouse aorta. Previous measurements of
O2 and induction by ANG II using lucigenin in the
range of 250-500 µM have been questioned because artifactual
production of O2 by lucigenin was observed under
conditions that skew quantification of enzyme-derived
O2 (24). Recent reports have
demonstrated that concentrations in the range of 5-50 µM do
not exhibit such artifactual O2 generation
(21), and thus we employed 25 µM lucigenin for all measurements. Consistent with previous findings in rats and rabbits (11, 34, 42), ANG II increased O2
production that was blocked by diphenylene iodonium, the
flavoprotein inhibitor of NAD(P)H oxidases, indicating increased
oxidase activity. The fact that the AT1 receptor antagonist
losartan was able to block this increase confirms previous reports in
rats that the AT1 receptor mediates the aortic response to
ANG II (38). Most studies were carried out in aortic rings
with SOD inhibited; however, we did detect increases in basal
O2 in these aortas. There was a greater degree of
variability in basal O2 that may be explained by
differing induction of SOD, which could compensate for the increased
production of O2. In fact, Fukai et al.
(9) recently reported that similar doses of ANG II
increase extracellular Cu,Zn SOD activity in this strain of mice at 7 days of treatment.
Phagocyte NAD(P)H oxidase is a multicomponent enzyme complex that
includes the two membrane-spanning polypeptide subunits, p22phox and gp91phox
(which together comprise flavocytochrome b558),
and three cytoplasmic polypeptide subunits,
p40phox, p47phox, and
p67phox (8, 45). Moreover, the
cytosolic guanine nucleotide-binding protein Rac2, a member of the Ras
family of peptides, is required for oxidase activation
(17). Exposure of the cell to a variety of agonists
stimulates the association of cytosolic and membrane-associated components and causes activation of the normally dormant and
unassembled oxidase (8, 45). It is generally well accepted
that dormant phagocyte NAD(P)H oxidase is activated by the assembly of
constitutively expressed components. We believe that vascular NAD(P)H
oxidase may differ in at least two ways: 1) the enzyme is
constitutively assembled and active under basal conditions; and
2) the components can be upregulated in response to hormonal
stimulation, leading to further assembly and enhanced oxidase activity.
The first contention is supported by our findings that nonstimulated
aortas containing the four major subunits of NAD(P)H oxidase possess
NAD(P)H oxidase activity and that immunodepletion of
p67phox from aortic membranes inhibits this
activity (34, 36). Second, we and other groups have shown
increased mRNA for p67phox and
p22phox and inferred that these increases
resulted in heightened O2-generating activity
(10, 33). However, the presence of mRNA for a particular
protein does not necessarily mean that the corresponding protein itself
is present (37). In fact, without detection of NAD(P)H
oxidase protein expression (34), involvement of NAD(P)H oxidase in vascular O2 production is less clear. In
the current study, Western blots showed a significant enhancement of
both p67phox and gp91phox
homologs in aortic homogenates from ANG II-infused versus
vehicle-infused and ANG II plus losartan-treated mice that correlated
positively with changes in O2 production, supporting
the suggestion of transcriptional and/or translational regulation of
these components. These increases would be expected to contribute to
higher NAD(P)H oxidase O2-generating activity,
because increases in individual components have been shown to enhance
NAD(P)H oxidase activity in cell-free assays (8).
Previous reports by other groups have shown that NAD(P)H oxidase(s)
exist in vascular smooth muscle cells (11, 27) and endothelial cells (15, 26). An NADH oxidase found in
vascular smooth muscle cells of the rat aorta seems to interfere with
vascular relaxation (38), and these cells express the mRNA
for one of the cytochrome b558 subunits found in
phagocyte membranes, p22phox (40).
In cultured rat aortic smooth muscle cells, NAD(P)H oxidase O2 activity is stimulated by ANG II and appears to be
involved in both the hypertrophic response (11, 40) and
the development of hypertension (20, 38). However, most
studies have focused on particular vascular segments or isolated cell
types in culture and did not determine the in situ location of this
activity under basal and stimulatory conditions. We have taken a
broader approach using nitroblue tetrazolium staining and
immunohistochemistry and have shown that the adventitia is the major
site of O2 production and cross-reactivity for all
four major components of NAD(P)H oxidase in the rabbit aorta (34,
36). Using in situ hybridization with cDNA for
p22phox, Fukui et al. (10) showed
that its mRNA was located in the media and adventitia, yet they did
not detect protein cross-reactivity of rat aortic tissue or smooth
muscle with antibodies raised against NAD(P)H oxidase components. Our
group also showed (using two distinct O2-detection
assays) that, in the rat, the adventitia is a major site of
O2 production and NAD(P)H oxidase component protein
expression under basal conditions and ANG II stimulation. Moreover,
those studies implicated adventitial O2 in the
destruction of endothelium-derived NO and the development of passive
tone during ANG II-dependent hypertension (42, 43). In the
present studies, we have confirmed those findings in the mouse aorta by
showing localization of gp91phox and
p67phox expression in the adventitia.
A large adventitial O2 source is highly relevant to
the bioactivity of endothelium-derived NO. Beckman and Koppenol
(1) described O2 as one of three major
scavengers of NO that act as a sink and lower its bioactive
concentrations over its diffusion radius of 100-200 µM
(19). This phenomenon is related to the ability of NO to
diffuse faster than it reacts with most biological substances. Thus
endothelial NO can rapidly diffuse to the adventitia and be inactivated
by O2 (because the adventitia exists within the
diffusion radius of NO). Because of its relatively high
O2-generating capacity compared with other vascular
sources, the adventitia could be expected to be a major impediment to
NO bioactivity throughout the vessel wall.
The adventitia has primarily been thought of as providing structure and
neural innervation to the underlying medial smooth muscle (13,
46), while its potential importance in the regulation of
NO-dependent vasodilatation and growth has long been ignored. Much of
the recent interest in the adventitia has been related to the
therapeutic success of endothelial NOS gene transfer in restoring
impaired vascular function (5, 32). However, our studies
have demonstrated that a major source of vascular O2
is adventitial fibroblasts, which in turn led to other studies documenting the importance of this source in the reduced bioactivity of
endothelium-derived NO (42, 43) in normotensive and
hypertensive rats. Together these findings imply a physiological role
for the adventitia in regulation of vascular tone. O2
from this source may also affect vascular NO derived from medial smooth
muscle cells (3, 29, 41) or from nitrergic
neurotransmission, which mediates arterial relaxation
(22). A resultant increase in peroxynitrite from rises in
NO and O2 may increase vascular tone in some vascular
beds but not in others, perhaps related to tissue-dependent differences
in guanylate cyclase activation (35). Studies are ongoing
to specifically address the involvement of adventitial NAD(P)H oxidase
in the development of vascular tone.
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ACKNOWLEDGEMENTS |
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We thank Drs. Marcos Alfie, Arash Kiarash, and Nagamasa Ogasawara for technical assistance with animal models and immunohistochemistry.
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FOOTNOTES |
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This work was supported by National Heart, Lung, and Blood Institute Grants R01 HL-55425 and HL-28982 and American Heart Association Grants 95011900 and 9808086W.
Address for reprint requests and other correspondence: P. J. Pagano, Division of Hypertension and Vascular Research, Rm. 7044, E & R Bldg., Henry Ford Hospital, 2799 W. Grand Blvd., Detroit, MI 48202-2689 (E-mail: ppagano1{at}hfhs.org).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 16 December 1999; accepted in final form 7 June 2000.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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