Heart Fail Rev (2011) 16:5–12
DOI 10.1007/s10741-010-9186-2
NADPH oxidases and cardiac remodelling
Adam Nabeebaccus • Min Zhang • Ajay M. Shah
Published online: 25 July 2010
 Springer Science+Business Media, LLC 2010
Abstract A heart under chronic stress undergoes cardiac
remodelling, a process that comprises structural and func-
tional changes including cardiomyocyte hypertrophy,
interstitial fibrosis, contractile dysfunction, cell death and
ventricular dilatation. Reactive oxygen species (ROS)-
dependent modulation of intracellular signalling is impli-
cated in the development of cardiac remodelling. Among the
different ROS sources that are present in the heart, NADPH
oxidases (NOXs) are particularly important in redox sig-
nalling. NOX isoforms are expressed in multiple cell types
including cardiomyocytes, fibroblasts, endothelial cells and
inflammatory cells—with the two main isoforms expressed
in the heart being NOX2 and NOX4. Recent studies indicate
that NOX-dependent signalling is involved in the develop-
ment of cardiomyocyte hypertrophy, interstitial fibrosis and
post-MI remodelling. NOXs may also be involved in the
genesis of contractile dysfunction and myocyte apoptosis.
Here, we review the main effects of NOXs in the patho-
genesis of cardiac remodelling and the redox-sensitive sig-
nalling pathways that underlie these effects. The elucidation
of mechanisms involved in NOX-dependent regulation of
cardiac remodelling may lead to new therapeutic targets for
heart failure.
Keyword Cardiac remodelling
NADPH oxidase

Reactive oxygen species
Oxidative stress

Redox signalling
A. Nabeebaccus
M. Zhang
A. M. Shah (&)
Cardiovascular Division, King’s College London British Heart
Foundation Centre, London SE5 9PJ, UK
e-mail: ajay.shah@kcl.ac.uk
A. Nabeebaccus
Cardiovascular Division, The James Black Centre, King’s
College London, 125 Coldharbour Lane, London SE5 9NU, UK
Introduction
Chronic heart failure is the culmination of a complex
interplay between various myocardial structural and func-
tional changes that are elicited in response to specific
stressors such as chronic pressure overload (e.g. due to
hypertension) or myocardial infarction (MI) [1]. These
changes are usually characterised by an initial adaptive
response of global or regional ventricular hypertrophy that
progresses to a series of maladaptive changes, including
interstitial fibrosis, contractile dysfunction, energetic defi-
cit, cardiomyocyte death, vascular dysfunction and cham-
ber dilatation. These maladaptive changes are collectively
termed adverse cardiac remodelling [2].
The process of remodelling is driven by complex
molecular mechanisms among which reactive oxygen
species (ROS)-dependent pathways have attracted signifi-
cant attention [3–5]. ROS include the free radicals super-
oxide anion (O•- •
2 ) and hydroxyl (OH ) as well as the highly
reactive compound hydrogen peroxide (H2O2). ROS exert
biological effects either by causing non-specific oxidative
damage to DNA, proteins, lipids and macromolecules or
through specific modulation of cellular signalling pathways
(termed redox signalling). Cellular levels of ROS and
therefore their effects are regulated by a variety of specific
and antioxidant systems (e.g. catalase, superoxide dismu-
tases, glutathione peroxidases, peroxiredoxins, thioredoxin
and various vitamins) [3]. Oxidative stress is said to exist
when there is an imbalance between ROS generation and
cellular antioxidant systems. An important concept with
respect to redox signalling is the idea that ROS production
occurs in a spatially and temporally regulated fashion
within the cell, so that the specific modulation of signalling
pathways results in discrete changes in cellular phenotype
[6].
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6 Heart Fail Rev (2011) 16:5–12
ROS can be produced by a variety of enzyme systems
that have been associated with heart failure, including
xanthine oxidase (XO) [7], mitochondria [8], uncoupled
nitric oxide synthases (NOSs) [9] and NADPH oxidases
(NOXs) [10]. The latter are a major source of ROS in the
cardiovascular system and are unique among the enzymes
mentioned in that they are especially important in redox
signalling [11]. Accumulating in vitro and in vivo evidence
suggests that NADPH oxidases play important roles in the
pathogenesis of cardiac remodelling. This includes studies
that have shown an increase in myocardial NADPH oxidase
expression and activity in experimental and human heart
failure [10], and more recent work that has used genetically
modified mouse models to provide more direct molecular
evidence for a causative role of NADPH oxidase in the
different components of cardiac remodelling [11]. These
studies suggest that NADPH oxidases are important in
modulating redox-sensitive signalling pathways involved in
remodelling.
NADPH oxidase structure and isoforms
NAPDH oxidase was first identified in neutrophils where it
generates ROS during phagocytosis and is involved in
microbicidal activity [12]. Subsequently, a total of five
NOX enzymes and two related dual oxidase enzymes
(DUOX) have been discovered [13]. The NOX enzymes
are each based on a distinct catalytic subunit (NOX1-5)—
Fig. 1. The prototypic phagocyte NADPH oxidase consists
of a highly glycosylated membrane-spanning NOX2 sub-
unit (originally called gp91phox) that forms a complex with
a smaller molecular weight protein called p22phox. The
heterodimer forms a flavocytochrome that catalyses the
transfer of electrons from NADPH to molecular oxygen,
thereby generating O.- 2 . The catalytic activity of the het-
erodimer is stimulated by the binding of regulatory
Fig. 1 Structure of NOX1-5
and requirement for regulatory
subunits. The structures are
based on predictions as no
crystal structure of any of the
NOX isoforms has yet been
solved. The haem moieties
facilitate the transfer of
electrons from NADPH and
FAD to molecular oxygen
123
cytosolic subunits (p47phox, p67phox, p40phox and Rac) [14].
Other NOX isoforms variably require the binding of dis-
tinct regulatory subunits for their activity [15, 16]. NOX1
binds to p22phox, Rac1 and to homologues of p47phox and
p67phox called NOXO1 and NOXA1. NOX3 can function
just as a heterodimer with p22phox, but its activity is
enhanced by interaction with p47phox and p67phox, although
it does not seem to require Rac [17]. NOX4 also binds to
p22phox but differs from the other NOXs in that it does not
require any other regulatory subunit for ROS production
and appears to be constitutionally active, with regulation
thought to occur mainly at transcriptional level [18].
Interestingly, recent reports suggest that NOX4 may have a
propensity for predominant H2O2 rather than O•- 2 produc-
tion, in marked contrast to NOX2 [18–20]. NOX5 is only
found in humans and not in rodents, does not require
p22phox for its activity, and has an extra calmodulin-like EF
domain in its N-terminal which confers calcium sensitivity.
Cardiovascular cells express a variety of NOX isoforms
[11]. NOX1 is found predominantly in vascular smooth
muscle cells, whereas NOX2 is expressed in endothelial
cells, cardiomyocytes and fibroblasts. NOX4 is expressed
in all the above-mentioned cell types, while NOX5 is
reported to be present in human endothelial cells and
vascular smooth muscle cells. An important caveat is that
much of the preceding is based on data from cultured cells
which may not necessarily reflect the physiological situa-
tion in vivo. For example, although NOX4 is readily
detected in cultured cardiomyocytes, its in vivo expression
in the healthy heart is very low. In general, NOXs (in
particular, NOX2) are activated by signalling pathways
downstream of G-protein coupled receptors such as
angiotensin II and endothelin 1, by cytokines (e.g. TNFa)
and/or mechanical forces. Following activation, ROS
generated by NOXs may modulate diverse signalling
pathways and redox-sensitive proteins (reviewed in
Anilkumar et al. [21]).
Heart Fail Rev (2011) 16:5–12
Role in cardiac hypertrophy
In isolated neonatal rat cardiomyocytes exposed to angio-
tensin II, NADPH oxidase activation was shown to be
involved in the ROS-dependent hypertrophic response [22].
NAPDH oxidase-mediated ROS production was also impli-
cated in a1-adrenoreceptor-stimulated hypertrophy of adult
rat ventricular myocytes [23]. These studies suggested that
NOX2 was involved in these effects. In a guinea-pig model of
pressure overload left ventricular hypertrophy (LVH), a sig-
nificant and sustained increase in NADPH oxidase activation
was found that correlated with increased expression of
NOX2, p22phox and p67phox, both in cardiomyocytes and in
coronary microvascular endothelial cells [24].
Studies using NOX2 knockout mice demonstrated more
compelling evidence for a role of NOX2 in mediating
hypertrophy. Compared to wild-type controls, NOX2-
deficient mice subjected to short-term subpressor infusion
of angiotensin II developed less LVH and lower increases
in molecular markers of hypertrophy, such as atrial natri-
uretic factor and b-myosin heavy chain mRNA [25]. Fur-
thermore, angiotensin II-induced increases in NADPH
oxidase activity were abolished in NOX2-deficient ani-
mals. Whereas this study was undertaken in mice globally
deficient in NOX2, supporting evidence for a role of car-
diomyocyte NOX2 in angiotensin II-induced hypertrophy
was provided by a study in isolated neonatal rat cardio-
myocytes in which siRNA directed against NOX2 abol-
ishing angiotensin II induced superoxide generation and
cardiomyocyte hypertrophy [26]. Additional in vivo data in
support of the importance of cardiomyocyte NOX2 was
provided by Satoh et al. [27] in a study that used inducible
cardiomyocyte-specific Rac1-deficient mice. This group
demonstrated that cardiomyocyte-specific deletion of Rac1
Fig. 2 Schematic showing
major signalling targets of
NADPH oxidase-derived ROS
in cardiac remodelling. RyR
Ryanodine receptor, SERCA
sarcoplasmic reticulum Ca2?
ATPase, MMP matrix
metalloproteinase, CTGF
connective tissue growth factor,
TGFb transforming growth
factor b
7
in adult mice inhibited angiotensin II-induced LVH as a
result of reduced NOX2 activation and ROS production.
Key NOX-modulated signalling pathways that contrib-
ute to the development of LVH appear to be the mitogen-
activated protein kinases (MAPKs), in particular ERK1/2,
and the phosphatidylinositol 3-kinase (PI3K)-Akt pathway
(Fig. 2) [22–27]. For example, a1-adrenoreceptor-stimu-
lated cardiomyocyte hypertrophy involves NADPH oxi-
dase-dependent activation of the Ras-MEK1/2-ERK1/2
pathway [23]. Interestingly, Ras may be a direct target of
ROS generated by NOXs as it was shown that a specific
thioredoxin-1-sensitive post-translational oxidative modi-
fication of thiols was involved in its activation [28].
Angiotensin II-induced cardiomyocyte hypertrophy was
also reported to involve NOX2-dependent Akt activation
[26]. The Rho GTPase Rac is critical for activation of
NOX2, and Rac1-induced hypertrophy of neonatal
cardiomyocytes involved the activation of ERK1/2 and
JNK signalling pathways [29], although whether this
involved NOX2 was not directly addressed in this study.
Apoptosis signal-regulating kinase 1 (ASK-1) is also
implicated in NOX-dependent signalling in cardiac
hypertrophy [27] and in fact mice deficient in ASK-1
showed impaired angiotensin II-induced JNK and
p38MAPK activation as well as reduced hypertrophy [30].
Activation of the transcription factors AP-1 and NFjB also
appears to be involved in NOX-dependent hypertrophy. In
neonatal rat ventricular myocytes, angiotensin II activated
AP-1 through NOX [2, 31, 32], although it remains unclear
whether this is a direct effect or occurs downstream of a
NOX2-activated signalling pathway. Cardiomyocyte
hypertrophy induced by GPCR agonists or by TNF-a,
which activates NOX2, is reported to be mediated via
NFjB activation [33].
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8 Heart Fail Rev (2011) 16:5–12
In contrast to angiotensin II-induced hypertrophy, NOX2
was found not to be essential for the development of pressure
overload LVH which was unaffected in NOX2 knockout
mice [34, 35]. Another study also reported that NOX2 did not
inhibit LVH in a model of chronic activation of the renin–
angiotensin system secondary to transgenic overexpression
of human renin [36]—which could be related to the pressure
overload present in this transgenic mouse model. Interest-
ingly, NADPH oxidase activity was still elevated in
NOX2-/- mice after aortic banding, which was attributed to
increased NOX4 expression [22], suggesting that NOX4
may also play some role in pressure overload LVH. How-
ever, preliminary results indicate that the two isoforms may
have distinct, non-redundant effects and that one isoform
does not necessarily compensate for the other. The results of
detailed studies using cell- and isoform-specific manipula-
tion of NOX2 and NOX4 will help to further define the
respective roles of these two isoforms.
Interstitial cardiac fibrosis
Interstitial cardiac fibrosis is a hallmark of adverse cardiac
remodelling and contributes to increased myocardial stiff-
ness, impaired diastolic and systolic function, and an
increased propensity for arrhythmias [1]. A significant body
of data implicates NOX2 NADPH oxidase in the develop-
ment of interstitial fibrosis in vivo. It was shown that NOX2
knockout mice had markedly reduced fibrosis compared to
wild-type animals in response to either subpressor or pressor
infusion of angiotensin II [25, 37]. Interestingly, in the
pressor model, interstitial fibrosis was inhibited in NOX2-
deficient mice even though the extent of LVH was similar to
wild-type controls [37], indicating a dissociation between
the pathways contributing to fibrosis and cardiomyocyte
hypertrophy. In the study by Satoh et al. [27] in cardiomy-
ocyte-specific Rac1 knockout mice, angiotensin II-induced
fibrosis was also inhibited, suggesting that in this case
cardiomyocytes NOX2 activation drove the fibrosis.
NOX2 was also implicated in aldosterone-induced
interstitial cardiac fibrosis [37]. Furthermore, Johar et al.
[37] found that angiotensin II-induced in vivo NADPH
oxidase activation and interstitial fibrosis in wild-type mice
were inhibited by treatment with the mineralocorticoid
receptor antagonist, spironolactone, despite a lack of
change in blood pressure or cardiac hypertrophy. This
finding suggests that mineralocorticoid receptor activation
is important downstream of angiotensin II in this model.
Studies in a rat model of aldosterone-induced fibrosis and
inflammation have also implicated NOX2 activation and
increased myocardial oxidative stress in the pathogenesis
of the fibrosis [38]. In a more recent study, apoptosis sig-
nal-regulating kinase 1 (ASK1)-deficient mice subjected to
123
aldosterone/salt treatment showed a marked reduction in
NOX2-associated ROS production with a significant
reduction in interstitial fibrosis and perivascular fibrosis
even though cardiac hypertrophy was similar to wild-type
mice [39]. In Dahl salt-sensitive rats fed on a high salt diet,
LV fibrosis was associated with an increased expression of
p22phox and NOX2 and increased NADPH oxidase activity
[40]. When Dahl sat-sensitive rats fed on a high salt diet
were treated with an eNOS enhancer, there was a decrease
in cardiac subunit expression of NOX2 and p22phox asso-
ciated with an attenuation in diastolic dysfunction, cardiac
hypertrophy and fibrosis [41]. Interstitial fibrosis is also
significantly attenuated in NOX2-deficient mice subjected
to aortic banding even though they have similar levels of
hypertrophy as their wild-type counterparts [42]. Taken
together, these studies indicate an important role of NOX2
in the development of in vivo interstitial cardiac fibrosis
occurring in response to diverse stimuli.
Johar et al. [37] found that interstitial cardiac fibrosis
induced by angiotensin II involved Nox2-dependent upreg-
ulation of profibrotic cytokines such as connective tissue
growth factor (CTGF) and profibrotic genes such as pro-
collagen-1, procollagen-3 and fibronectin (Fig. 2). They also
found that there was increased Nox2-dependent activation of
NF-jB and MMP2. MMP2 is implicated in cardiac remod-
elling and has importance in modulating cardiomyocyte
function including causing contractile dysfunction and
apoptosis [43]. It has also been shown to be activated by
NOX via JNK/p38/ERK1/2 signalling in cardiac myocytes
exposed to doxorubicin (a cardiotoxic anticancer drug that
can cause heart failure) [44]. The NOX2-expressing cell
types that are involved in the development of fibrosis (i.e.
fibroblasts, cardiomyocytes, inflammatory cells and/or
endothelial cells) remain to be defined.
In contrast to above-mentioned studies, some in vitro
studies suggest an important role for NOX4 in the devel-
opment of cardiac fibrosis. Cucoranu et al. [45] in a study
involving cultured human cardiac fibroblasts found that
NOX4 and 5 mRNAs were abundantly expressed, whereas
NOX1 and 2 were barely detectable. These authors repor-
ted that TGF-b1 upregulated NOX4 expression and pro-
moted the conversion of fibroblasts to myofibroblasts,
which are the main producers of collagen in the extracel-
lular matrix. This study implied that NOX4 may be
responsible for driving cardiac fibrosis in response to TGF-
b1 stimulation, the latter being well established as a driver
of cardiac fibrosis [46]. However, TGF-b may also have
beneficial actions as evidenced by data that TGF-b inhi-
bition is detrimental in mice after MI [47]. It should be
noted that NOX2 is expressed in mouse cardiac fibroblasts
and that TGF-b1 enhanced expression of p22phox, p47phox
and NOX2 as well as collagen formation by these cells,
which could be reduced by NOX2 siRNA [48]. To
Heart Fail Rev (2011) 16:5–12
determine whether both NOX2 and NOX4 are involved in
the development of interstitial fibrosis or whether there are
differences between mouse and human fibroblasts or
whether in vitro studies fail to reflect the complex in vivo
setting in which fibrosis develops requires further studies.
Contractile dysfunction
The development of contractile dysfunction is an important
feature of cardiac decompensation during chronic exposure
to stress and a hallmark of adverse cardiac remodelling [1].
Several studies suggest that NADPH oxidase activation may
contribute to the development of contractile dysfunction in
cardiac hypertrophy and heart failure. In a guinea-pig model
of LVH, increased myocardial NADPH oxidase activity was
shown to contribute to impaired coronary endothelial func-
tion and thereby to impaired ventricular relaxation [49].
Along similar lines, Cheng et al. [50] reported that NADPH
oxidase activation contributed to increased diastolic stiffness
in the Dahl salt-sensitive rat model of hypertensive heart
failure, although the mechanism was proposed to involve
changes in the extracellular matrix. In NOX2-deficient mice
subjected to aortic banding, Grieve et al. [42] found evidence
of significantly better contractile function than wild-type
animals both in whole hearts and at the level of isolated
cardiomyocytes. The contractile dysfunction in wild-type
animals could be acutely improved by antioxidant treatment,
suggesting that there were direct effects of increased ROS on
contractile function in this setting. NADPH oxidase activa-
tion has also been implicated in the development of con-
tractile dysfunction in myocardial depression associated
with gram-negative sepsis [51, 52], obesity [53] and strep-
tozotocin-induced diabetes [54].
The mechanisms underlying NOX-dependent contractile
dysfunction remain to be fully defined. Abnormalities of
cardiomyocyte excitation–contraction coupling, mitochon-
drial dysfunction, myocyte apoptosis and/or alterations in
the extracellular matrix could all contribute depending
upon the context. With respect to excitation–contraction
coupling, it is known that ROS can modulate the function
of sarcolemmal ion channels, the sarcoplasmic reticulum
(SR) calcium release channel (the ryanodine receptor), the
SR calcium pump (SERCA 2a) and contractile proteins
themselves [55, 56]. Recently, it has also been reported that
ROS may modulate CAMkinase II, possibly via NOX [57].
Cardiomyocyte apoptosis
Apoptosis of cardiomyocytes is considered to be an
important contributor to the development of fibrosis and
contractile dysfunction on the failing heart [58]. In
9
neonatal rat cardiomyocytes exposed to angiotensin II,
increased NADPH oxidase expression and activity were
reported to contribute to apoptosis [59]. The specific NOX
isoform involved was not identified, but the involvement
of p47phox suggests that it may be NOX2. A similar
pro-apoptotic effect of aldosterone in neonatal rat cardio-
myocytes was also suggested to involve NADPH oxidase-
derived ROS production [60]. NADPH oxidase-derived
ROS were also implicated in cardiomyocyte apoptosis
induced by the chemotherapeutic agent doxorubicin [61].
Likewise, in cultured adult rat cardiomyocytes exposed to
high glucose as a model of diabetic cardiomyopathy,
upregulation of Rac1 and NOX2 oxidase activity contrib-
uted to apoptosis [62, 63].
The potential mechanisms involved in NOX-dependent
pro-apoptotic effects remain to be fully defined [21]. In
neonatal rat cardiac myocytes exposed to aldosterone, it
was suggested that NOX-dependent ROS production pro-
moted apoptosis via activation of ASK-1 [60]. In angio-
tensin II-induced cardiomyocyte apoptosis, the activation
of p38MAPK, increase in Bcl-2, decrease in Bax and
caspase-3 activity were proposed to be NOX dependent,
based on the use of apocynin [59].
Post-MI remodelling
Cardiac remodelling occurring after myocardial infarction
involves all the features described previously, namely
cardiomyocyte hypertrophy, fibrosis and apoptosis. In
addition, a major feature is extracellular matrix remodel-
ling and dilatation of the heart. Numerous studies support
an important role for increased ROS in this process [64].
NOX2 and associated oxidase subunit expression have
been shown to be increased at sites of infarcted myocar-
dium in a rat model [65] as well as in humans who had died
from acute myocardial infarction [66]. In the latter study, at
least part of the expression was in cardiomyocytes. Direct
evidence to support a role for NOX2 in post-MI remodel-
ling comes from studies in p47phox-deficient and NOX2-
deficient mice. Doerries et al. [67] found that p47phox-
knockout mice had better preserved contractile function,
reduced LV remodelling and higher survival than wild-type
controls after MI, despite similar infarct size. This was
associated with a reduction in cardiomyocyte hypertrophy,
apoptosis and interstitial fibrosis. Similarly, Looi et al. [68]
found that NOX2-deficient mice were also protected
against contractile dysfunction and LV remodelling post-
MI when compared to wild-type mice, again despite a
similar infarct size. NOX2-deficient mice also had less
cardiomyocyte hypertrophy, apoptosis and interstitial
fibrosis. Frantz et al. [69] also studied the response to MI in
Nox2-deficient mice but reported no benefit of Nox2
123
10
deletion. However, it should be noted that these authors did
not use littermate controls nor did they include a sham-
operated group for either genotype. Dandapat et al. [70]
found that overexpression of TGF-b1 in mouse cardio-
myocytes reduced NADPH oxidase activation and ROS
production after hypoxia–reoxygenation, with a concomi-
tant reduction in apoptosis. These authors also found that in
vivo rodent hearts transfected with TGF-b1 and then
exposed to ischaemia–reperfusion injury developed
reduced NADPH oxidase activation and smaller infarct
size compared to non-transfected rodents. TGF-b1 is gen-
erally regarded to be pro-fibrotic; however, in this model
the effect was cardioprotective both in vitro and in vivo and
involved NADPH oxidase although the NOX isoform and
underlying mechanisms remain unclear. NADPH oxidase
activation has also been reported to contribute to the
exacerbation of post-MI heart failure in mice with type 2
diabetes compared to non-diabetic mice [71].
Conclusions and clinical implications
The NADPH oxidases have emerged as important players
in modulating redox-sensitive signalling pathways
involved in the processes of cardiac remodelling. They
influence several aspects of this complex process, including
cardiomyocyte hypertrophy, contractile dysfunction,
apoptosis and interstitial fibrosis. In vivo studies with NOX
enzyme-deficient mice have begun to demonstrate the
functional relevance of these alterations in signalling. In
this regard, it would be attractive to selectively target
detrimental aspects of the process of adverse cardiac
remodelling, such as fibrosis or cardiomyocyte apoptosis.
In fact, some of the beneficial effects of existing therapies
for heart failure, such as ACE inhibitors and angiotensin
receptor blockers, could in part relate to inhibition of
NOX2-dependent signalling since angiotensin II is a key
activator of the enzyme. Statins (3-hydroxy-3-methylglu-
taryl coenzyme A reductase inhibitors) also inhibit NOX2
activation although evidence that they are beneficial in
clinical heart failure is still lacking [72]. The complexity of
regulation of NOX enzymes may paradoxically provide
additional ways of therapeutically manipulating enzyme
activity. A better understanding of the biochemical func-
tion of these fascinating enzymes as well as their roles in
cardiac remodelling may lead to new therapeutic targets
based on modulation of NOX activity.
Acknowledgments The authors’ work is supported by the British
Heart Foundation (RG/08/011/25922, CH/99001; RE/08/003), a
Leducq Foundation Transtlantic Network of Excellence Award, and
EU FP6 grant LSHM-CT-2005-018833 (EUGeneHeart).
123
Heart Fail Rev (2011) 16:5–12
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