Activation of NADPH Oxidase During Progression of

Cardiac Hypertrophy to Failure

Jian-Mei Li, Nick P. Gall, David J. Grieve, Mingyou Chen, Ajay M. Shah

Abstract—Increased reactive oxygen species (ROS) production is implicated in the pathophysiology of left ventricular
(LV) hypertrophy and heart failure. However, the enzymatic sources of myocardial ROS production are unclear. We
examined the expression and activity of phagocyte-type NADPH oxidase in LV myocardium in an experimental guinea
pig model of progressive pressure-overload LV hypertrophy. Concomitant with the development of LV hypertrophy,
NADPH-dependent O2⫺ production in LV homogenates, measured by lucigenin (5 ␮mol/L) chemiluminescence or
cytochrome c reduction assays, significantly and progressively increased (by ⬇40% at the stage of LV decompensation;
P⬍0.05). O2⫺ production was fully inhibited by diphenyleneiodonium (100 ␮mol/L). Immunoblotting revealed a
progressive increase in expression of the NADPH oxidase subunits p22phox, gp91phox, p67phox, and p47phox in the LV
hypertrophy group, whereas immunolabeling studies indicated the presence of oxidase subunits in cardiomyocytes and
endothelial cells. In parallel with the increase in O2⫺ production, there was a significant increase in activation of
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extracellular signal–regulated kinase 1/2, extracellular signal–regulated kinase 5, c-Jun NH2-terminal kinase 1/2, and
p38 mitogen-activated protein kinase. These data indicate that an NADPH oxidase expressed in cardiomyocytes is a
major source of ROS generation in pressure overload LV hypertrophy and may contribute to pathophysiological changes
such as the activation of redox-sensitive kinases and progression to heart failure. (Hypertension. 2002;40:477-484.)
Key Words: hypertrophy 䡲 free radicals 䡲 heart failure 䡲 myocardium 䡲 reactive oxygen species

A n increase in oxidative stress resulting from increased

cardiac generation of reactive oxygen species (ROS) is
implicated in the pathophysiology of pressure-overload left
ventricular hypertrophy (LVH) and congestive heart failure,
both experimentally and in clinical studies.1–3 Increased ROS
production is implicated in the development of cellular
hypertrophy and remodeling, at least in part through activa-
tion of redox-sensitive protein kinases such as the mitogen-
activated protein kinase (MAPK) superfamily. The transition
from compensated pressure-overload LVH to heart failure is
associated with increased oxidative stress, which may pro-
mote myocyte apoptosis and necrosis. Several key proteins
involved in excitation-contraction coupling, such as sar-
colemmal ion channels and exchangers and sarcoplasmic
reticulum calcium release channels, can undergo redox-
sensitive alterations in activity, which contributes to myocar-
dial contractile dysfunction. ROS also has indirect effects
resulting from increased inactivation of NO and consequent
generation of peroxynitrite, eg, coronary vascular endothelial
dysfunction and peroxynitrite-induced inhibition of myocar-
dial respiration.4
The sources of ROS generation that contribute to these
effects in pressure-overload LVH and heart failure remain
poorly defined. Potential sources include the mitochondrial
electron transport chain, xanthine oxidase, cytochrome
P450 – based enzymes, dysfunctional NO synthases (NOSs),
and infiltrating inflammatory cells such as neutrophils. Re-
cently, a major source of ROS production in cardiovascular
cells such as vascular smooth muscle, endothelium, and
adventitial fibroblasts has been shown to be a phagocyte-type
NADPH oxidase.5– 8 The prototypic NADPH oxidase com-
plex consists of a core heterodimer comprising 1 p22phox and
1 gp91phox subunit, and 4 regulatory subunits—p40phox, p47phox,
p67phox, and rac1.9 In vascular smooth muscle, the gp91phox
subunit is replaced by 1 of 2 homologs termed Nox1 and
Nox4.5 The ROS-generating activity of vascular smooth
muscle and endothelial NADPH oxidases is increased by
stimuli such as angiotensin II, tumor necrosis factor-␣,
growth factors and cyclical load. Vascular NADPH oxidases
are implicated in the development of angiotensin II–induced
vascular smooth muscle hypertrophy, hypertension, endothe-
lial dysfunction, and atherosclerosis.5
Whether a similar NADPH oxidase is expressed in the
heart, particularly in cardiomyocytes, and whether it plays a
role in the pathophysiology of LVH and heart failure have
received little attention. Some studies have provided bio-
chemical evidence for the presence of a phagocyte-type
NADPH oxidase in cardiomyocytes, but the molecular nature

Received May 17, 2002; first decision June 7, 2002; revision accepted July 23, 2002.
From the Department of Cardiology, Guy’s King’s & St Thomas’ School of Medicine (Denmark Hill Campus), King’s College London, London,
United Kingdom.
Correspondence to Ajay M Shah MD, FRCP, Department of Cardiology, GKT School of Medicine (Denmark Hill Campus), Bessemer Road, London
SE5 9PJ, United Kingdom. E-mail ajay.shah@kcl.ac.uk
© 2002 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org DOI: 10.1161/01.HYP.0000032031.30374.32

477
 478 Hypertension October 2002
of the enzyme was not addressed.10,11 Recently, we reported
that experimental angiotensin II–induced cardiac hypertrophy
was inhibited in gene-modified mice lacking the gp91phox
subunit of NADPH oxidase.12 However, the response of
NADPH oxidase to the more clinically relevant stimulus of
chronic pressure overload is unknown. Furthermore, it is
unclear what cardiac cell types the oxidase is expressed in or
what changes occur in oxidase expression and activity during
development of hypertrophy.
The aims of the present study were to investigate the
following in an experimental model of progressive pressure-
overload LVH: (1) whether alterations in expression and
activity of NADPH oxidase contribute to increased ROS
generation during progression to decompensated LVH and
failure, (2) whether the oxidase is expressed in cardiomyo-
cytes, and (3) the relationship between ROS generation and
potential functional consequences such as activation of
redox-sensitive MAPKs.
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Methods
Experimental Hypertrophy
All procedures were performed in accordance with the Guidance on
the Operation of the Animals (Scientific Procedures) Act 1986 (Her
Majesty’s Stationery Office, London, United Kingdom). Male
Dunkin-Hartley guinea pigs (200 to 250 g; Harlan UK Ltd, Bicestor,
UK) underwent suprarenal abdominal aortic banding or sham band-
ing.13 Aortic banding in guinea pigs is a well-established model of
pressure-overload LVH that has been preferred over small rodent
models in several studies because guinea pig LV more closely
resembles human myocardium with respect to myosin heavy-chain
isoform expression and electrophysiological characteristics. In this
model, compensated LVH is present from 2 weeks after surgery
followed by a transition phase from 4 to 6 weeks and then overt LV
decompensation at 8 to 10 weeks.13 Animals from the banded and
sham groups were euthanized at 1, 3, 6, and 10 weeks postopera-
tively for harvesting of heart tissue. LV and right ventricular weights,
lung weight, and body weight were determined, and tissue for
immunoblotting, immunohistochemistry, or biochemistry was snap-
frozen in liquid N2 and stored at ⫺70°C until study.
Protein extraction and Immunoblotting
LV protein samples were prepared as described previously without
Triton X-100.14 The antibodies against p22phox, CD31, phospho-
extracellular signal–regulated kinase (ERK) 1/2, phospho– c-Jun
NH2-terminal kinase (JNK), and ERK5 were from Santa Cruz
Biotechnology; antibodies to gp91phox, p40phox, p47phox, and rac1 were
kind gifts from Dr F Wientjes (University College London, United
Kingdom); the monoclonal anti-p67phox was a kind gift from Dr M
Quinn (Montana State University, Bozeman, Mont). Human neutro-
phil membrane protein (kindly provided by Dr F Wientjes) was the
positive control for p22phox and gp91phox, and the protein extract from
human phagocytic U937 cells after phorbol 12-myristate 13-acetate
stimulation was the positive control for the other subunits. An
anti-cardiac troponin I monoclonal antibody was kindly provided by
Dr I Trayer (University of Birmingham, United Kingdom). The
anti-␣-tubulin monoclonal was from Sigma; and the anti-phospho-
p38 MAPK antibody was from Cell Signaling Technology.
Immunohistochemistry
Samples were prepared as described previously.15 Frozen sections
were first treated with a Biotin Blocking kit (DAKO) according to
manufacturer instructions. Primary antibodies were used at 1:50 to
1:250 dilution in 0.1% BSA/PBS for 30 minutes at room tempera-
ture. Biotin-conjugated anti-rabbit, anti-goat, or anti-mouse IgG
(1:500 dilution) was used as a secondary and was detected by a
StreptABCcomplex/HRP kit (DAKO). For immunofluorescence
staining, specific binding was detected by fluorescein isothiocya-
nate– or tetramethyl rhodamine isothiocyanate (TRITC)-labeled
extravidin (green and red fluorescence, respectively). Normal rabbit
or mouse IgG (5 ␮g/mL) was used instead of primary antibody as a
negative control. Images were acquired on a Zeiss microscope
coupled to a digital imaging system (Improvision, United Kingdom).
Lucigenin Chemiluminescence
O2-production by LV tissue homogenate (n⫽6 hearts per group at
each time point) was measured using lucigenin-enhanced chemilu-
minescence in a microplate luminometer (Anthos Lucy 1, Austria).16
A low lucigenin concentration (5 ␮mol/L) was employed to mini-
mize artifactual O2⫺ production owing to redox cycling. Briefly,
proteins were diluted in modified HEPES buffer and distributed (100
␮g/well) onto a 96-well microplate. NADPH (100 ␮mol/L) and
dark-adapted lucigenin were added to wells just before reading. O2⫺
production was expressed as arbitrary light units over 20 minutes.
Some experiments were performed in the presence of superoxide
dismutase (SOD, 200 U/mL) or a cell-permeable superoxide scav-
enger, tiron (10 mmol/L). The following agents were used in some
experiments to assess potential sources of O2⫺ production: diphe-
nyleneiodonium (100 ␮mol/L), a flavoprotein inhibitor that blocks
NADPH oxidase; the NOS inhibitor NG-nitro-L-arginine methyl ester
(100 ␮mol/L); an inhibitor of the mitochondrial electron chain,
rotenone (50 ␮mol/L); or a xanthine oxidase inhibitor, oxypurinol
(100 ␮mol/L). All studies were performed in triplicate.
Cytochrome c Reduction Assay
NADPH-dependent O2- production was also examined using SOD-
inhibitable cytochrome c reduction.16 LV tissue homogenate (final
concentration 1 mg/mL) diluted in Dulbecco’s modified Eagle’s
medium without phenol red was distributed in 96-well plates (final
volume, 200 ␮L/well). Cytochrome c (500 ␮mol/L) and NADPH
(100 ␮mol/L) were added in the presence or absence of SOD (200
U/mL) and incubated at room temperature for 30 minutes. Cyto-
chrome c reduction was measured by reading absorbance at 550 nm
on a microplate reader.
Statistics
All data are presented as mean⫾SD from ⱖ6 animals in each group
at each time point after the operation (except anywhere mentioned in
the text). Comparisons were made by unpaired t test, with Bonfer-
onni correction for multiple testing, or by 1-way ANOVA as
appropriate. P⬍0.05 was considered significant.
Results
NADPH-Dependent ROS Generation During
Progression of LVH
As reported previously,13 LV/body weight ratio was signifi-
cantly higher by 3 weeks after surgery in the banded group
compared with the sham group. Lung/body weight ratio was
increased in the banded group by 10 weeks after surgery
(Figure 1A and 1B). Body weights were similar in bands and
shams at each stage (data not shown).
NADPH-dependent O2⫺ production by LV homogenates
assessed by lucigenin chemiluminescence was significantly
increased in the banded group by 3 weeks after surgery,
concomitant with development of LVH, and had increased
further by 6 weeks after surgery (Figure 1C). No further
increase in ROS production was observed between 6 and 10
weeks.
Similar results were obtained with the cytochrome c
reduction and lucigenin assays. Figure 2A shows a compar-
ison of ROS production measured by cytochrome c reduction
or lucigenin chemiluminescence at the 10-week stage.
 Li et al
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Figure 1. Relationship between the development of pressure-
overload LVH and myocardial NADPH oxidase activity. Changes
in LV/body weight ratio (A) and lung/body weight ratio (B) after
aortic banding; n⫽6 per group at each stage. C, NADPH-
dependent O2⫺ production by LV tissue homogenate measured
by lucigenin (5 ␮mol/L) chemiluminescence. MLU indicates
mean arbitrary light units. *P⬍0.05 vs respective sham controls
(unpaired t test with Bonferroni correction).
Enzymatic sources of NADPH-dependent ROS production
were examined using specific inhibitors in the lucigenin
assay. Figure 2B shows results for the 10-week stage (similar
results were obtained at 3 and 6 weeks). ROS production was
NADPH Oxidase and Pressure Overload LVH 479
abolished either by tiron or diphenyleneiodonium, and was
substantially reduced by SOD, both in the banded and sham
groups. Rotenone and oxypurinol had no effect in either
group. Interestingly, there was a slight (17⫾11%) but signif-
icant (P⬍0.05) reduction in NADPH-dependent ROS produc-
tion in the presence of NG-nitro-L-arginine methyl ester in the
banded group.
Protein Expression of NADPH Oxidase Subunits
LV tissue homogenates from the same hearts as used for
measuring ROS production were used for immunoblotting.
All 5 subunits of NADPH oxidase—ie, p22phox, gp91phox,
p67phox, p47phox, p40phox, and rac1—were detectable in both
groups using anti-human neutrophil antibodies (Figure 3).
gp91phox in guinea pig LV tissue migrated as a band at 75 kDa
and 2 bands of higher apparent molecular weight (mw) at
⬇90 to 100 kDa, which was broadly similar to the pattern
for neutrophil membrane protein. p47phox was detected as a
doublet band, both in guinea pig myocardium and U937
cells. The expression of p22phox, gp91phox, p67phox, and
p47phox became progressively higher in the LVH group
compared with shams with increasing LVH (Figures 3 and
4). Interestingly, p22phox, gp91phox, and p67phox expression
appeared to increase earlier than did p47phox, which did not
increase until 6 weeks after surgery. The expression level
of p40phox and rac1 was similar in the 2 groups.
To assess which cell types in the heart expressed NADPH
oxidase subunits, we undertook immunohistochemistry on
LV sections from sham and LVH groups. Figure 5A shows
the expression of gp91phox detected by peroxidase histostain-
ing in sham (top) and LVH (middle) at 10 weeks after
surgery. It is evident that gp91phox was expressed within the
cardiac myocytes and that the level of expression was higher
in LVH tissue compared with shams. Similar results were
obtained with immunofluorescence staining (data not shown).
p67phox and p47phox were also expressed in cardiomyocytes
(data not shown). NADPH oxidase subunits were also ex-
pressed in endothelial cells, albeit at a lower level. Figure 5B
Figure 2. Enzymatic sources of myocardial
NADPH-dependent ROS production pro-
duction. A, O2⫺ production by LV tissue
homogenate at 10-week postoperative
stage, measured in parallel by SOD-
inhibitable cytochrome c reduction (top)
and lucigenin chemiluminescence (bottom).
B, Effect of various agents on NADPH-
dependent O2⫺ production by LVH and
sham group tissue. Data are expressed rel-
ative to baseline level in the absence of
inhibitor (ie, 100%). *P⬍0.05 by 1-way
ANOVA; n⫽6 per group.
 480 Hypertension October 2002

Figure 3. Representative immunoblots showing

changes in expression of NADPH oxidase sub-
units in guinea pig LV tissue during LVH progres-
sion. Cardiac troponin I expression was used as a
loading control. Neutrophil membrane extract was
used as a positive control for p22phox and
gp91phox, and phorbol 12-myristate 13-acetate–
stimulated U937 cell protein was used for the
other subunits.
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shows LV sections double immunolabeled with a goat poly- rabbit polyclonal anti-p22phox antibody (green fluorescence;
clonal anti-CD31 antibody as a specific endothelial cell Figure 5B, right). Superimposition of the images indicates
marker17 (red fluorescence) and either a monoclonal anti- that p67phox and p22phox were expressed both in coronary
p67phox antibody (green fluorescence; Figure 5B, left) or a endothelium and cardiomyocytes.

Figure 4. Changes in protein expression of p22phox, gp91phox, p67phox, p47phox, p40phox, and rac1 during LVH progression. Immunoblots
from 3 independent sets of experiments (n⫽9) were densitometrically scanned, and the results were expressed as mean⫾SD. All 3
bands were scanned for gp91phox. Cardiac troponin I detected in the same sample was used as a loading control. *P⬍0.05 vs respec-
tive sham controls by unpaired t test with Bonferroni correction.
 Li et al NADPH Oxidase and Pressure Overload LVH 481
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Figure 5. Immunolabeling of LV myocardial sections for the cellular expression of NADPH oxidase subunits. A, Immunohistochemical
sections of LV at 10 weeks after surgery labeled for the myocardial expression of gp91phox in sham-banded (top) and LVH (middle)
hearts. Same LVH tissue section labeled with normal rabbit IgG as a background control (bottom). B, Immunofluorescence images of
LVH sections at 10-week stage double-labeled with an anti-endothelial cell marker CD31 (red color) plus an anti-p67phox antibody (green
color, left) or an anti-p22phox antibody (green color, right). The superimposed images indicate co-localization of the markers (yellow
color) and additional anti-p67phox and anti-p22phox labeling in cardiomyocytes. Bottom, Negative controls labeled with nonspecific mouse
IgG and goat IgG.

Changes in Expression and Phosphorylation of Discussion

p38-MAPK, ERK1/2, JNK, and ERK5 During the
Development of LVH and Heart Failure
To investigate the possible relationship between NADPH
oxidase activation and the activation of redox-sensitive ki-
nases, we measured the phosphorylation of ERK1/2, p38-
MAPK, JNK, and ERK5 (Figure 6). The levels of phosphor-
ylated ERK1/2 increased significantly in LV myocardium of
the banded group compared with shams by 3 weeks after
surgery and continued to increase further with progression of
LVH and heart failure. The expression of ERK5 and
phospho-p38 MAPK was significantly increased in LVH
samples at 6 and 10 weeks after surgery. The levels of
phosphorylated JNK increased significantly during the early
stages of LVH but declined during the phase of LV decom-
pensation (10 weeks).
The major findings of the present study are that (1) all the
main components of a functional phagocyte-type NADPH
oxidase are expressed in guinea pig myocardium, notably in
cardiomyocytes; (2) NADPH oxidase– derived ROS genera-
tion increases significantly in pressure overload LVH, at least
partly as a result of increased expression of oxidase compo-
nents; and (3) the increase in myocardial NADPH oxidase
activity is paralleled by activation of the redox-sensitive
kinases ERK1/2, ERK5, and p38 MAPK and by progression
of cardiac hypertrophy. Collectively, these findings suggest
that NADPH oxidase activation may play an important
pathophysiological role in progressive pressure-overload
LVH and heart failure.
Although a phagocyte-type NADPH oxidase has been
demonstrated in many cardiovascular cell types,5– 8 previous
data for its expression in cardiomyocytes were mainly bio-
 482 Hypertension October 2002
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chemical.10,11 In a recent study, cardiac mRNA expression of
p22phox and gp91phox was reportedly increased after myocardial
infarction; however, this was probably related to increased
neutrophil infiltration, whereas evidence of cardiomyocyte
expression was not reported.18 In the current study, we show
that all the main subunits of the phagocyte-type NADPH
oxidase (including gp91phox) are expressed at protein level in
guinea pig myocardium, and that the cell types in which the
oxidase is expressed include the cardiomyocyte.
Although increased ROS production during progressive
pressure-overload LVH is well recognized, the sources of
these ROS have been unclear. In this study, we clearly
demonstrated that a phagocyte-type NADPH oxidase was a
major ROS source. Interestingly, a small but significant
proportion (⬇17%) of NADPH-dependent ROS production
could be inhibited by an NOS inhibitor, suggesting that
dysfunctional NOS activity may also partly contribute to
ROS production.19 This is not surprising because it has been
suggested that ROS production from any source may induce
dysfunctional O2⫺-generating NOS activity, as a consequence
of ROS-dependent degradation of the essential NOS cofactor
tetrahydrobiopterin.20 Potential mechanisms through which
Figure 6. Changes in expression of
phospho-p38 MAPK, phospho-
ERK1/2, phospho-JNK1/2, and ERK5
during LVH progression. A, Represen-
tative immunoblot showing the expres-
sion of phospho-p38 MAPK, phospho-
ERK1/2, phospho-JNK1/2, and ERK5.
␣-Tubulin expression was used as a
loading control. B, Densitometric anal-
yses of expression levels from 3 inde-
pendent sets of experiments (n⫽9),
expressed as mean⫾SD. *P⬍0.05 vs
respective sham controls by unpaired t
test with Bonferroni correction.
NADPH oxidase activity is increased include transcriptional
upregulation of oxidase components and posttranslational
modifications, such as p47phox phosphorylation and rac1
translocation.9 In the present study, at least part of the
mechanism underlying the increased NADPH oxidase activ-
ity was an increase in expression of p22phox, gp91phox, p67phox,
and p47phox. Stimuli that augment NADPH oxidase activity in
the peripheral vasculature and may be relevant to pressure-
overload LVH include angiotensin II, tumor necrosis
factor-␣, and mechanical stretch.5 The relative contribution of
these stimuli to the upregulation observed in the present study
requires further investigation.
An increase in ROS production may have several potential
effects in the hypertrophying heart. In isolated cardiomyo-
cytes, a moderate increase in ROS induces hypertrophy and
apoptosis.21 Angiotensin II– and tumor necrosis factor-␣–
induced hypertrophy of cultured cardiomyocytes is abrogated
by antioxidants.22,23 Recently, we reported that angiotensin II
induced in vivo cardiac hypertrophy was inhibited in gp91phox-
null mice.12 The mitogenic effects of ROS may involve
modulation of redox-sensitive signaling pathways such as Src
kinases and MAPKs (including ERK1/2, ERK5, and p38
 Li et al
MAPK), which leads to activation of transcriptional fac-
tors.3,24,25 The subsequent changes in gene expression may
account for many of the changes in LVH. Activation of
redox-sensitive signaling pathways may also be implicated in
the transition of compensated LVH to heart failure. In the
present study, increased myocardial NADPH oxidase activity
was accompanied by activation of ERK1/2, ERK5, and p38
MAPK. ERK1/2 has been implicated in cardiac hypertro-
phy,3,25–27 being induced by increased pressure28 and Gq-
coupled receptor agonists.29 ERK1/2 and ERK5 are signifi-
cantly activated by H2O2 perfusion in the isolated guinea pig
heart.30 Although many studies have proposed that ROS
mediates cardiomyocyte hypertrophic response to agonist
stimulation via the ERK cascade,3,26,27 the mechanisms that
couple hypertrophic signals to activation of ERK signaling
and gene expression remain unclear. The current results
suggest that agonist-induced activation of NADPH oxidase
may be an important upstream component of the pathway
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leading to activation of redox-sensitive MAPKs such as
ERK1/2 and ERK5. Interestingly, in the present study,
ERK1/2 activation was observed quite early at the stage of
compensated LVH, whereas activation of p38 MAPK and
ERK5 occurred at the transition stage between compensated
and decompensated LVH. This could reflect a differential
involvement of these kinases in hypertrophy versus transition
to heart failure.31 In addition, we found that while activation
of JNK was observed early during LVH, during the develop-
ment of failure the levels of phospho-JNK declined despite
maintained NADPH oxidase activity. This finding suggests
dissociation between NADPH oxidase– derived ROS produc-
tion and the activation of specific MAPKs.
Another important consequence of increased ROS produc-
tion is endothelial dysfunction resulting from increased inac-
tivation of NO.19 It is of interest that we found NADPH
oxidase expression not only in cardiomyocytes but also in
coronary microvascular endothelium. Indeed, it is well rec-
ognized that endothelial cells express NADPH oxidase and
produce O2⫺,5–7,19,32 and we have recently reported that
increased endothelial ROS production may contribute to
impaired LV relaxation in pressure-overload LVH.33
Perspectives
This is the first study to report a progressive activation of
NADPH oxidase in the myocardium in pressure overload
LVH and suggests that this enzyme system may play a role in
myocardial pathophysiology analogous to reports of its im-
portance in the vasculature. NADPH oxidase– derived ROS
may potentially contribute to several aspects of the patho-
physiology of LVH and heart failure. In particular, activation
of redox-sensitive signaling molecules such as ERK1/2,
ERK5, and p38 MAPK may be involved in the development
of hypertrophy and/or transition to heart failure.
To define the precise contribution of NADPH oxidase-
derived in LVH and the mechanisms underlying upregulation
of NADPH oxidase activity after imposition of pressure
overload, it will be necessary to undertake appropriate studies
in experimental models, including gene-modified animals.
The possibility that targeting myocardial NADPH oxidase
NADPH Oxidase and Pressure Overload LVH 483
expression and activity may provide a means of modifying
development of LVH and heart failure merits investigation.
Acknowledgments
This work was supported by British Heart Foundation (BHF)
program grant RG/98008. N.P.G. was supported by a BHF Junior
Fellowship. A.M.S. holds the BHF Chair of Cardiology in King’s
College London.
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Hypertension. 2002;40:477-484; originally published online August 26, 2002;

doi: 10.1161/01.HYP.0000032031.30374.32
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