Karen Bedard and Karl-Heinz Krause
Karen Bedard and Karl-Heinz Krause
Karen Bedard and Karl-Heinz Krause
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Thus, although it is hard to extrapolate from these measurements<br />
to the in vivo situation, it is conceivable that<br />
under hypoxic conditions, ROS generation by NOX enzymes<br />
drops. However, from a mechanistic point of view,<br />
this traditional hypothesis is difficult to reconcile with<br />
observations that 1) HIF is activated by ROS (136), 2)<br />
increased ROS levels mimick the inhibition of redoxsensitive<br />
K � channels by hypoxia (912), <strong>and</strong> 3) NOX4<br />
overexpression enhances hypoxic inhibition of the<br />
TASK-1 K � channel (519).<br />
A revised model where hypoxia increases ROS generation<br />
is depicted in Figure 6. Such a hypoxia-induced<br />
ROS generation, while counterintuitive, has now been<br />
amply documented (337, 362, 455, 581, 941). The source of<br />
the hypoxia-induced ROS might be mitochondria <strong>and</strong>/or<br />
NOX enzymes. There are solid arguments for both suggestions.<br />
In favor of a role of mitochondria, suppression<br />
of the mitochondrial cytochrome-c oxidase suppresses<br />
hypoxia-induced ROS generation in various cell lines<br />
(115, 337, 579). In favor of a role of NOX enzymes, studies<br />
using primary mouse carotid body chemoreceptor cells<br />
demonstrate that moderate hypoxia leads to increased<br />
ROS generation that is absent in cells derived from<br />
p47 phox -deficient mice (362). The mechanisms accounting<br />
for hypoxia activation of NOX-dependent ROS generation<br />
are not understood.<br />
1. Kidney<br />
In the kidney, hypoxia-dependent posttranslational<br />
stabilization of the transcription factor HIF1� leads to<br />
transcriptional activation of the erythropoietin gene, a<br />
key mechanism for the regulation of erythropoiesis. There<br />
are no mechanistic experiments demonstrating a role of<br />
NOX4 in oxygen sensing by the kidney, but such a role is<br />
conceivable based on the NOX4 localization in the kidney<br />
cortex (294, 813).<br />
2. Carotid body<br />
Carotid bodies are sensory organs composed of a<br />
small cluster of cells located near the bifurcation of the<br />
carotid artery. Carotid bodies detect changes in arterial<br />
oxygen saturation <strong>and</strong> respond to hypoxia by inducing<br />
tachycardia <strong>and</strong> increased ventilation. The carotid body is<br />
composed primarily of two cell types: the glomus cells,<br />
which act as the primary oxygen-sensing cells, <strong>and</strong> the<br />
sustentacular cells, which surround the innervated glomus<br />
cells (713). A decrease in oxygen is rapidly sensed by<br />
the glomus cells, resulting in Ca 2� -dependent neurotransmission<br />
<strong>and</strong> ultimately in increased respiratory <strong>and</strong> cardiac<br />
function.<br />
Molecules <strong>and</strong> mechanisms implied in oxygen sensing<br />
in the carotid body include hemoxygenase (571), nitric<br />
oxide synthetase (712), the mitochondrial respiratory<br />
THE NOX FAMILY OF ROS-GENERATING NADPH OXIDASES 269<br />
Physiol Rev VOL 87 JANUARY 2007 www.prv.org<br />
chain (45), a direct ion channel modulation by oxygen<br />
(559, 695), <strong>and</strong> NOX enzymes.<br />
Early theories suggested a role for NOX2, which can<br />
be detected in carotid bodies (7, 174, 490); however, the<br />
presence of NOX2 in carotid bodies probably reflects the<br />
presence of macrophages (236). Several studies suggest<br />
normal oxygen sensing in NOX2-deficient mice (32, 361,<br />
760), <strong>and</strong> there are no reports of any oxygen-sensing<br />
deficits in patients with CGD. However, while NOX2 deficiency<br />
does not alter oxygen sensing, there are two<br />
studies suggesting an altered oxygen-sensing in p47 phox -<br />
deficient mice (362, 775). The apparent discrepancy between<br />
NOX2-deficient mice <strong>and</strong> p47 phox -deficient mice<br />
hints at a role of a p47 phox -dependent NOX isoform other<br />
than NOX2.<br />
3. Pulmonary oxygen sensing<br />
In pulmonary neuroepithelial bodies, oxygen sensing<br />
involves redox regulation of K � currents. In this<br />
system, there is relatively strong evidence for an involvement<br />
of NOX2 in oxygen sensing: in NOX2-deficient<br />
mice, there is a decreased response to hypoxia in<br />
newborn animals (449) <strong>and</strong> in cells from neuroepithelial<br />
bodies (275). This NOX2 dependence of oxygen<br />
sensing appears to be specific for the pulmonary neuroepithelial<br />
bodies, as oxygen sensing was not impaired<br />
in pulmonary artery smooth muscle from NOX2-deficient<br />
mice (32).<br />
4. Others<br />
No role for NOX2 in oxygen sensing was observed<br />
in Epstein-Barr virus (EBV)-transformed B lymphocytes<br />
(946) or in cardiac fibroblasts (761). Endogenously<br />
expressed NOX in HEK293 is suggested to<br />
cooperate with the TASK-1 K � channel in oxygen sensing.<br />
This effect can be abolished by the expression of<br />
NOX4 siRNA <strong>and</strong> enhanced by overexpression of NOX4<br />
but not NOX2 (519).<br />
G. Biosynthesis <strong>and</strong> Protein Cross-Linking<br />
Peroxidation reactions are important in physiology.<br />
One of the best-documented roles for NOX enzymes<br />
is the iodination of thyroid hormones, a reaction<br />
catalyzed by the thyroid peroxidase using DUOX-derived<br />
hydrogen peroxide (189, 228, 630). Another example<br />
is the H 2O 2 <strong>and</strong> peroxidase-dependent cross-linking<br />
of dityrosine residues in the extracellular matrix, which<br />
has been shown to be DUOX-dependent in cutaneous<br />
tissue of Caenorhabditis elegans (239). Dityrosine<br />
cross-linking is also important for the hardening of the<br />
fertilization envelope in sea urchin eggs, where it is<br />
mediated by the DUOX homolog Udx1 (957). Whether<br />
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