Nox4 Is a Major Source of Superoxide Production in Human Brain Pericytes

Kuroda, Junya; Ago, Tetsuro; Nishimura, Ataru; Nakamura, Kuniyuki; Matsuo, Ryu; Wakisaka, Yoshinobu; Kamouchi, Masahiro; Kitazono, Takanari

doi:10.1159/000369930

Cited by 60 publications

(49 citation statements)

References 36 publications

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“…Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit 4 (NOX4) is one of the proteins responsible for the ROS production in cerebral tissue [14]. The expression level of NOX4 in 10%O 2 was twice that in 21%O 2 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Among the mechanisms underlying the redox imbalance in hypoxic cerebral tissue, the mitochondrial complex I may be relevant [28], but NOX4, which nearly doubled from 21%O 2 to 10%O 2 , is likely a pivotal factor because it responds directly to hypoxia [29] and stands out as the main enzyme family that is dedicated to forming ROS [30], thereby constituting a major ROS source [14], [31]. On the other hand, Nrf2, one of the genes that are altered in rat brains after 12 h high altitude exposure [32], may represent a major mechanism that regulates antioxidant defenses [17].…”

Section: Discussionmentioning

confidence: 99%

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Brain adaptation to hypoxia and hyperoxia in mice

et al. 2017

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AimsHyperoxic breathing might lead to redox imbalance and signaling changes that affect cerebral function. Paradoxically, hypoxic breathing is also believed to cause oxidative stress. Our aim is to dissect the cerebral tissue responses to altered O2 fractions in breathed air by assessing the redox imbalance and the recruitment of the hypoxia signaling pathways.ResultsMice were exposed to mild hypoxia (10%O2), normoxia (21%O2) or mild hyperoxia (30%O2) for 28 days, sacrificed and brain tissue excised and analyzed. Although one might expect linear responses to %O2, only few of the examined variables exhibited this pattern, including neuroprotective phospho- protein kinase B and the erythropoietin receptor. The major reactive oxygen species (ROS) source in brain, NADPH oxidase subunit 4 increased in hypoxia but not in hyperoxia, whereas neither affected nuclear factor (erythroid-derived 2)-like 2, a transcription factor that regulates the expression of antioxidant proteins. As a result of the delicate equilibrium between ROS generation and antioxidant defense, neuron apoptosis and cerebral tissue hydroperoxides increased in both 10%O2 and 30%O2, as compared with 21%O2. Remarkably, the expression level of hypoxia-inducible factor (HIF)−2α (but not HIF-1α) was higher in both 10%O2 and 30%O2 with respect to 21%O2InnovationComparing the in vivo effects driven by mild hypoxia with those driven by mild hyperoxia helps addressing whether clinically relevant situations of O2 excess and scarcity are toxic for the organism.ConclusionProlonged mild hyperoxia leads to persistent cerebral damage, comparable to that inferred by prolonged mild hypoxia. The underlying mechanism appears related to a model whereby the imbalance between ROS generation and anti-ROS defense is similar, but occurs at higher levels in hypoxia than in hyperoxia.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Brain adaptation to hypoxia and hyperoxia in mice

et al. 2017

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“…The fact that Nox4 expression increased in the diabetic ApoE −/− kidney in this study may seem contradictory. However, two reports claim that NOX4 contributes to the generation of superoxide under some disease conditions [34,35], highlighting the important nature of changes in ROS production between health and disease. H 2 O 2 levels were also observed to increase in the aorta after 30 mg kg −1 day −1 GKT137831 treatment.…”

Section: Discussionmentioning

confidence: 99%

Combined NOX1/4 inhibition with GKT137831 in mice provides dose-dependent reno- and atheroprotection even in established micro- and macrovascular disease

et al. 2017

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Aims/hypothesis Oxidative stress is a promising target in diabetes-associated vasculopathies, with inhibitors of NADPH oxidases (NOX), in particular isoforms 1 and 4, shown to be safe in early clinical development. We have explored a highly relevant late-stage intervention protocol using the clinically most advanced compound, the NOX1/4 inhibitor GKT137831, to determine whether end-organ damage can be reversed/attenuated when GKT137831 is administered in the setting of established diabetic complications. Methods GKT137831 was administered at two doses, 30 mg kg −1 day −1 and 60 mg kg −1 day −1

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“…Nox proteins are well-established sources for ROS in various vascular diseases including brain injury [15, 16, 20, 37]. Several studies showed that enhanced Nox4 expression was accompanied with an increase not only in hydrogen peroxide but also superoxide [38–42]. Nox4 silencing has been a promising strategy in improving neurovascular outcomes following I/R injury [21–23].…”

Section: Discussionmentioning

confidence: 99%

Nox4 contributes to the hypoxia-mediated regulation of actin cytoskeleton in cerebrovascular smooth muscle

Coucha

Abdelsaid

et al. 2016

Life Sciences

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Ischemia/reperfusion and the resulting oxidative/nitrative stress impair cerebral myogenic tone via actin depolymerization. While it is known that NADPH oxidase (Nox) family is a major source of vascular oxidative stress; the extent and mechanisms by which Nox activation contributes to actin depolymerization, and equally important, the relative role of Nox isoforms in this response is not clear. Aim To determine the role of Nox4 in hypoxia-mediated actin depolymerization and myogenic-tone impairment in cerebral vascular smooth muscle. Main methods Control and Nox4 deficient (siRNA knock-down) human brain vascular smooth muscle cells (HBVSMC) were exposed to 30-min hypoxia/45-min reoxygenation. Nox2, Nox4, inducible and neuronal nitric oxide synthase (iNOS and nNOS) and nitrotyrosine levels as well as F:G actin were determined. Myogenic-tone was measured using pressurized arteriography in middle cerebral artery isolated from rats subjected to sham, 30-min ischemia/45-min reperfusion or ex-vivo oxygen glucose deprivation in the presence and absence of Nox inhibitors. Results Nox4 and iNOS expression were significantly upregulated following hypoxia or ischemia/reperfusion. Hypoxia augmented nitrotyrosine levels while reducing F actin. These effects were nullified by inhibiting nitration with epicatechin or pharmacological or molecular inhibition of Nox4. Ischemia/reperfusion impaired myogenic-tone, which was restored by the selective inhibition of Nox4. Conclusion Nox4 activation in VSMCs contributes to actin depolymerization after hypoxia, which could be the underlying mechanism for myogenic-tone impairment following ischemia/reperfusion.

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Nox4 Is a Major Source of Superoxide Production in Human Brain Pericytes

Cited by 60 publications

References 36 publications

Brain adaptation to hypoxia and hyperoxia in mice

Brain adaptation to hypoxia and hyperoxia in mice

Combined NOX1/4 inhibition with GKT137831 in mice provides dose-dependent reno- and atheroprotection even in established micro- and macrovascular disease

Nox4 contributes to the hypoxia-mediated regulation of actin cytoskeleton in cerebrovascular smooth muscle

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