Editorial
Hydrogen Peroxide
Watery Fuel for Change in Vascular Biology
Frank M. Faraci
C
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branes may occur via aquaporins.6 Both short- and long-term
effects of H2O2 on vascular cells continue to be explored. For
example, H2O2 produces relaxation of many blood vessels, but
can produce vasoconstriction depending on the species, the
segment of the vasculature, and the concentration of H2O2
(Figure).7,24 –31 Vasodilation in response to H2O2 can occur
indirectly through endothelium-dependent relaxation or via direct effects on vascular muscle, possibly including formation of
calcium sparks.24,25,27–29 H2O2 can mediate vascular responses to
varied stimuli including endothelium-dependent agonists, increases in blood flow,25,30,32 and arachidonic acid.33 H2O2 may
contribute to increases in myogenic tone with increases in blood
pressure.34 In addition to promoting the formation of other vasodilators, H2O2 may function as one of a family of endothelium-derived
hyperpolarizing factors.35,36 Along with effects on vascular tone,
H2O2 can increase permeability of endothelium.21,37
Regarding more long-term effects, H2O2 has the potential to alter
expression of many genes,38 including some thought to play a major
role in vascular biology (Figure). For example, H2O2 activates
transcription factors including NF-␬B,17 stimulates expression of
endothelial and inducible isoforms of NO synthase (eNOS and
iNOS, respectively)39 – 41 and components of NAD(P)H oxidase.42 Substantial evidence suggests that H2O2 functions as a
mediator of vascular growth contributing to vascular hypertrophy during hypertension (Figure).19,21 Whether H2O2 plays a role
in other structural changes such as inward vascular remodeling is
unclear. H2O2 may play a larger role in the development and
progression of atherosclerosis than does superoxide43 and may
contribute to vascular injury and cell death, particularly after
conversion to hydroxyl radical (Figure).44 Interestingly, the rate
of cardiovascular events in patients with atherosclerosis is
inversely related to activity of glutathione peroxidase in erythrocytes,45 which is consistent with a role for H2O2 in vascular
disease.
Although ROS can themselves alter vascular tone, these
molecules can also impair vasomotor responses to other stimuli.
The impact of superoxide on endothelial function continues to be
a major area of research focus. Wei and Kontos provided the
first evidence that ROS can impair endothelium-dependent
relaxation.46 Superoxide reacts highly efficiently with NO (Figure), reducing its bioavailability for further signaling.2,3 Studies
using exogenous application of H2O2 or mice deficient in
expression of glutathione peroxidase suggest that H2O2 can also
impair NO-mediated signaling in blood vessels.47–50 Nevertheless, the mechanism(s) by which H2O2 impairs endothelial
function are likely to be more complex. For example, H2O2 may
impair endothelium-dependent relaxation after conversion to
hydroxyl radical.47,48 H2O2 can stimulate NAD(P)H oxidase in
vascular cells (Figure),21,51,52 reduce levels of tetrahydrobiopterin,53 and thus may promote uncoupling of eNOS, further
ells within the vessel wall have the capacity to produce
a variety of reactive oxygen species (ROS: superoxide
anion, hydrogen peroxide [H2O2], hydroxyl radical,
etc).1–3 In diverse experimental models and in patients with
disease, levels of ROS in blood vessels increase and contribute
to vascular pathophysiology.1–3 Although not widely appreciated
initially, it has become increasing apparent that relatively low
concentrations of ROS can function as signaling molecules,4 –7
and thus may be involved with normal regulation of vascular
structure and function.
See page 2035
Superoxide can be produced by multiple enzymatic and
non-enzymatic sources and is the precursor for many ROS
including the highly reactive hydroxyl radical (Figure). In
addition to the rate of production, steady state levels of ROS are
also determined by the activity of an array of antioxidant
enzymes including superoxide dismutases (SOD) which convert
superoxide to H2O2 (Figure).8,9 H2O2 levels are regulated by
catalase and a group of glutathione peroxidases which metabolize H2O2 to water (Figure).7–10
Discovered in 1818 by the French chemist Louis-Jacques
Thenard,11 H2O2 has a wide array of uses including as an
antiseptic, a bleaching agent, in food processing, and as a fuel for
rockets.12 Much more recently, the role of H2O2 in vascular
biology has begun to be appreciated and better defined. In both
disease models and in normal aging, local concentrations of H2O2
increase in blood vessels and in vascular cells in culture.13–19
Although SOD activity is a major source of H2O2 (Figure), there
may be other sources as well. For example, ROS in vascular cells
can be produced by NAD(P)H oxidases (Figure)20–22 and the
NAD(P)H oxidase containing Nox4 [NAD(P)H oxidase 4] may
predominantly produce H2O2, rather than superoxide (Figure).23
Increasing evidence suggests that H2O2 may play diverse and
important roles in vascular biology. Water and H2O2 share many
physical features.6 The addition of a second oxygen atom to
water (described as “oxygenated water” by Thenard), however,
results in a molecule with many distinct chemical and biological
properties. Similar to nitric oxide (NO), H2O2 is chemically more
stable than superoxide and other ROS.5,6 H2O2 is also relatively
cell permeable, although some movement through cell memFrom the Departments of Internal Medicine and Pharmacology,
Cardiovascular Center, University of Iowa Carver College of Medicine,
Iowa City.
Correspondence to Frank M. Faraci, PhD, Department of Internal
Medicine, E315-GH, University of Iowa, Carver College of Medicine,
Iowa City, Iowa 52242-1081. E-mail [email protected]
(Arterioscler Thromb Vasc Biol. 2006;26:1931-1933.)
© 2006 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol. is available at http://www.atvbaha.org
DOI: 10.1161/01.ATV.0000238355.56172.b3
1931
1932
Arterioscler Thromb Vasc Biol.
September 2006
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Schematic summary of selected changes within the vessel wall
in relation to H2O2. Superoxide (O2⫺) is produced from molecular
oxygen by a variety of sources including NAD(P)H oxidase
(Nox). Superoxide can react with nitric oxide (NO) to form peroxynitrite (ONOO⫺). H2O2 is formed from the activity of superoxide dismutases (SOD) or possibly directly by NAD(P)H oxidase
containing Nox4. H2O2 can be degraded to water by glutathione
peroxidases (GPx) or catalase (Cat). H2O2 can exert multiple
effects in blood vessels including: (1) amplify oxidative stress by
further increasing expression and activity of NAD(P)H oxidase,
(2) form hydroxyl radical (via an iron dependent process), a
highly reactive free radical species, (3) increase expression of
arginase, thus reducing levels of L-arginine available to NO synthases, (4) increase or decrease vascular tone, (5) alter expression of clusters of genes, and (6) increase vascular growth
(hypertrophy). See text for details.
increasing the levels of superoxide.52,53 This increase in superoxide presumably results in a feed-forward mechanism that
further amplifies oxidative stress (Figure).
The recent study by Thengchaisi et al in this issue of Arteriosclerosis, Thrombosis, and Vascular Biology suggests an additional
mechanism by which H2O2 may impair endothelial function.54 In
this study, exogenous application of H2O2 both increased expression of arginase I and selectively decreased endotheliumdependent (NO-mediated) responses in coronary arterioles. Arginases metabolize L-arginine to urea and L-ornithine,55 so
increased activity of the enzyme may reduce availability of
L-arginine needed for production of NO (L-arginine is the
substrate for NO production). Pharmacological inhibitors of
arginase or exogenous L-arginine restored endothelial function
in arterioles treated with H2O2. Additional experiments with
deferoxamine suggested that hydroxyl radical may actually be
the mediator of the H2O2-induced vascular dysfunction.
Several question arise from this work. The concentration of
H2O2 needed to produce these effects (100 ␮mol/L) was relatively high and may be supraphysiological.5 Studies of ROS are
sometimes criticized for the use of high levels of H2O2. In
addition, the extracellular application of exogenous H2O2 may
not completely mimic effects of endogenously produced H2O2
because of the compartmentalization of ROS effects.8,56 Thus, a
key unanswered question is whether levels of endogenously
formed H2O2 are sufficient to produce similar effects on the
vasculature. Considering the array of mechanisms that have been
implicated in previous studies (see above), can endothelial
dysfunction in response to H2O2 be fully explained by changes in
activity of arginase? Through what mechanism does H2O2 or
oxidative stress increase expression and activity of arginase?
There are two isoforms of arginase, and RT-PCR data suggested
that only arginase I is expressed in coronary arterioles. Other
studies indicate, however, that both arginase I and II are
expressed in vascular cells, and this expression can change in
disease.57–59 Thus, the question of the relative importance of
different arginase isoforms under physiological and pathophysiological conditions remains unanswered. Most studies, including the study be Thengchaisi,54 used pharmacological inhibitors
that do not discriminate between arginase isoforms.
In summary, oxidative stress in the vasculature is common in
diverse experimental models and occurs in diseased blood
vessels in humans. Because of their complex interrelationships,
it has been difficult to fully define the role of specific ROS in
blood vessels. There is increasing interest into the role of H2O2
in vascular biology, both as a signaling molecule and a mediator
of vascular disease and altered growth. The wide variety of
effects that H2O2 has in vascular cells is already impressive in
scope but continues to grow.
Acknowledgments
The author thanks Dr Jon Andresen for critical evaluation of
this manuscript.
Sources of Funding
Work reviewed in this manuscript from this laboratory was supported by National Institutes of Health grants HL-38901, NS-24621,
HL-62984, and by a Bugher Foundation Award in Stroke from the
American Heart Association (0575092N).
Disclosures
None.
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Hydrogen Peroxide: Watery Fuel for Change in Vascular Biology
Frank M. Faraci
Arterioscler Thromb Vasc Biol. 2006;26:1931-1933
doi: 10.1161/01.ATV.0000238355.56172.b3
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