-
[show abstract]
[hide abstract]
ABSTRACT: NADPH oxidase Nox4 is expressed in a wide range of tissues and plays a role in cellular signaling by providing reactive oxygen species (ROS) as intracellular messengers. Nox4 oxidase activity is thought to be constitutive and regulated at the transcriptional level; however, we challenge this point of view and suggest that specific quinone derivatives could modulate this activity. In fact, we demonstrated a significant stimulation of Nox4 activity by 4 quinone derivatives (AA-861, tBuBHQ, tBuBQ, and duroquinone) observed in 3 different cellular models, HEK293E, T-REx™, and chondrocyte cell lines. Our results indicate that the effect is specific toward Nox4 versus Nox2. Furthermore, we showed that NAD(P)H:quinone oxidoreductase (NQO1) may participate in this stimulation. Interestingly, Nox4 activity is also stimulated by reducing agents that possibly act by reducing the disulfide bridge (Cys226, Cys270) located in the extracellular E-loop of Nox4. Such model of Nox4 activity regulation could provide new insight into the understanding of the molecular mechanism of the electron transfer through the enzyme, i.e., its potential redox regulation, and could also define new therapeutic targets in diseases in which quinones and Nox4 are implicated.
Biochemical pharmacology 04/2013; · 4.25 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Aims: Psychosocial stress alters the HPA-axis. Increasing evidence shows a link between these alterations and oxidant elevation. Oxidative stress is implicated in the stress-response and in the pathogenesis of neurologic and psychiatric diseases. NOX enzymes are a major source of ROS in the CNS. Here, we investigated the contributory role of NOX2-derived ROS to the development of neuroendocrine alterations in a rat model of chronic psychosocial stress, the social isolation. Results: Significant elevations in the hypothalamic levels of CRF and plasmatic ACTH were observed from four weeks of social isolation. Increased levels of peripheral markers of the HPA-axis (plasmatic and salivary corticosterone) were observed at later time point of social isolation (seven weeks). Alteration in exploratory activity of isolated rats followed the same time course. Increased expression of markers of oxidative stress (8OhdG and nitrotyrosine) and NOX2 mRNA was early detectable in the hypothalamus of isolated rats (after two weeks), but later (after seven weeks) in the adrenal gland. A three-weeks-treatment with the antioxidant/NOX inhibitor apocynin stopped the progression of isolation-induced alterations of the HPA-axis. Rats with a loss of function mutation in the NOX2 subunit p47phox were totally protected from alterations of the neuroendocrine profile, behavior and increased NOX2 mRNA expression induced by social isolation. Innovation: We demonstrate that psychosocial stress induces early elevation of NOX2-derived oxidative stress in the hypothalamus and consequent alterations of the HPA-axis, leading ultimately to altered behavior. Conclusion: Pharmacological targeting of NOX2 might be of crucial importance for treatment of psychosocial stress-induced psychosis.
Antioxidants & Redox Signaling 01/2013; · 8.20 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: NADPH oxidases synthesize reactive oxygen species that may participate in fibrosis progression. NOX4 and NOX2 are NADPH oxidases expressed in the kidneys, with the former being the major renal isoform, but their contribution to renal disease is not well understood. Here, we used the unilateral urinary obstruction model of chronic renal injury to decipher the role of these enzymes using wild-type, NOX4-, NOX2-, and NOX4/NOX2-deficient mice. Compared with wild-type mice, NOX4-deficient mice exhibited more interstitial fibrosis and tubular apoptosis after obstruction, with lower interstitial capillary density and reduced expression of hypoxia-inducible factor-1α and vascular endothelial growth factor in obstructed kidneys. Furthermore, NOX4-deficient kidneys exhibited increased oxidative stress. With NOX4 deficiency, renal expression of other NOX isoforms was not altered but NRF2 protein expression was reduced under both basal and obstructed conditions. Concomitant deficiency of NOX2 did not modify the phenotype exhibited by NOX4-deficient mice after obstruction. NOX4 silencing in a mouse collecting duct (mCCD(cl1)) cell line increased TGF-β1-induced apoptosis and decreased NRF2 protein along with expression of its target genes. In addition, NOX4 silencing decreased hypoxia-inducible factor-1α and expression of its target genes in response to hypoxia. In summary, these results demonstrate that the absence of NOX4 promotes kidney fibrosis, independent of NOX2, through enhanced tubular cell apoptosis, decreased microvascularization, and enhanced oxidative stress. Thus, NOX4 is crucial for the survival of kidney tubular cells under injurious conditions.
Journal of the American Society of Nephrology 10/2012; · 9.66 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: NADPH oxidases (NOX) are superoxide anion radical (O(2)(-•))-generating enzymes. They form a family of seven members, each with a specific tissue distribution. They function as electron transport chains across membranes, using NADPH as electron donor to reduce molecular oxygen to O(2)(-•). NOX have multiple biological functions, ranging from host defense to inflammation and cellular signaling. Measuring NOX activity is crucial in understanding the roles of these enzymes in physiology and pathology. Many of the methods used to measure NOX activity are based on the detection of small molecules that react with NOX-generated O(2)(-•) or its direct dismutation product hydrogen peroxide (H(2)O(2)) to form fluorescent, luminescent, or colored products. Initial techniques were developed to measure the activity of the phagocyte isoform NOX2 during the oxidative burst of stimulated polymorphonuclear leukocytes, which generate large quantities of O(2)(-•). However, other members of the NOX family generate much less O(2)(-•) and hence H(2)O(2), and their activity is difficult to distinguish from other sources of these reactive species. In addition, O(2)(-•) and H(2)O(2) are reactive molecules and most probes are prone to artifacts and therefore should be used with appropriate controls and the data carefully interpreted. This review gives an overview of current methods used to measure NOX activity and NOX-derived O(2)(-•) and H(2)O(2) in cells, tissues, isolated systems, and living organisms, describing the advantages and caveats of many established methods with emphasis on more recent technologies and future perspectives.
Free radical biology & medicine 09/2012; 53(10):1903-1918. · 5.42 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Abstract Significance: Severe life stress (SLS), as opposed to trivial everyday stress, is defined as a serious psychosocial event with the potential of causing an impacting psychological traumatism. Recent Advances: Numerous studies have attempted to understand how the central nervous system (CNS) responds to SLS. This response includes a variety of morphological and neurochemical modifications; among them, oxidative stress is almost invariably observed. Oxidative stress is defined as disequilibrium between oxidant generation and the antioxidant response. Critical Issues: In this review, we discuss how SLS leads to oxidative stress in the CNS, and how the latter impacts pathophysiological outcomes. We also critically discuss experimental methods that measure oxidative stress in the CNS. The review covers animal models and human observations. Animal models of SLS include sleep deprivation, maternal separation, and social isolation in rodents, and the establishment of hierarchy in non-human primates. In humans, SLS, which is caused by traumatic events such as child abuse, war, and divorce, is also accompanied by oxidative stress in the CNS. Future Directions: The outcome of SLS in humans ranges from resilience, over post-traumatic stress disorder, to development of chronic mental disorders. Defining the sources of oxidative stress in SLS might in the long run provide new therapeutic avenues. Antioxid. Redox Signal. 00, 000-000.
Antioxidants & Redox Signaling 07/2012; · 8.20 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Chronic granulomatous disease (CGD), caused by a lack of reactive oxygen species (ROS) generation by the phagocyte NADPH oxidase NOX2, leads to massively increased inflammatory responses. In order to identify the type of phagocyte which requires NOX2 activity to limit inflammation, we investigated mice with a loss of function mutation in the Ncf1 gene coding for the p$47^{\rm{phox}}$ subunit of NOX2 and mice with transgenic rescue of Ncf1 under control of the CD68 promoter. To induce CGD hyperinflammation, different mouse genotypes were injected intradermally with β-glucan. Ncf1 mutant mice showed massive and prolonged hyperinflammation. Hyperinflammatory lesions were characterized by persistent neutrophilic infiltration, along with ulceration and necrosis. In contrast, in CD68 promoter rescue mice inflammation resolved within days, as seen in wild-type animals. Measurements of ROS in rescue mice demonstrated functional NOX2 in mononuclear phagocytes (macrophages and dendritic cells) but not in neutrophils. This absence of NOX2 function was also confirmed in inflammatory tissue neutrophils. Lack of functional NOX2 in mononuclear phagocytes increased the secretion of IL-1β at early time points and of IL-6 and TNFα at later time points. Thus, CGD hyperinflammation is a redox dysregulation in mononuclear phagocytes, demonstrating a cell type-specific anti-inflammatory function of NOX2. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
The Journal of Pathology 06/2012; 228(3):341-50. · 6.32 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Among the pathogenic mechanisms underlying central nervous system (CNS) diseases, oxidative stress is almost invariably described. For this reason, numerous attempts have been made to decrease reactive oxygen species (ROS) with the administration of antioxidants as potential therapies for CNS disorders. However, such treatments have always failed in clinical trials. Targeting specific sources of reactive oxygen species in the CNS (e.g. NOX enzymes) represents an alternative promising option. Indeed, NOX enzymes are major generators of ROS, which regulate progression of CNS disorders as diverse as amyotrophic lateral sclerosis, schizophrenia, Alzheimer disease, Parkinson disease, and stroke. On the other hand, in autoimmune demyelinating diseases, ROS generated by NOX enzymes are protective, presumably by dampening the specific immune response. In this review, we discuss the possibility of developing therapeutics targeting NADPH oxidase (NOX) enzymes for the treatment of different CNS pathologies. Specific compounds able to modulate the activation of NOX enzymes, and the consequent production of ROS, could fill the need for disease-modifying drugs for many incurable CNS pathologies.
Cellular and Molecular Life Sciences CMLS 05/2012; 69(14):2387-407. · 6.57 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: High expectations surround the area of stem cells therapeutics. However, the cells' source-adult or embryonic-and the cells' origin-patient-derived autologous or healthy donor genetically unrelated-remain subjects of debate. Autologous origins have the advantage of a theoretical absence of immune rejection by the recipient. However, this approach has several limitations with regard to the disease of the recipient and to potential problems with the generation, expansion, and manipulation of autologous induced pluripotent stem cells (iPS cells) preparation. An alternative to using autologous cells is the establishment of a bank of well-characterized adult cells that would be used to generate iPS cells and their derivatives. In the context of transplantation, such cells would come from genetically unrelated donors and the immune system of the recipient would reject the graft without immunosuppressive therapy. To minimize the risk of rejection, human leukocyte antigen (HLA) compatibility is certainly the best option, and the establishment of an HLA-organized bank would mean having a limited number of stem cells that would be sufficient for a large number of recipients. The concept of haplobanking with HLA homozygous cell lines would also limit the number of HLA mismatches, but such an approach will not necessarily be less immunogenic in terms of selection criteria, because of the limited number of HLA-compatible loci and the level of HLA typing resolution.
Stem cells and development 05/2012; 21(13):2364-73. · 4.15 Impact Factor
-
Homa Attar,
Karen Bedard,
Eugenia Migliavacca,
Maryline Gagnebin,
Yann Dupré,
Patrick Descombes,
Christelle Borel,
Samuel Deutsch,
Holger Prokisch,
Thomas Meitinger,
Divya Mehta,
Erich Wichmann,
Jean Maurice Delabar,
Emmanouil T Dermitzakis, Karl-Heinz Krause,
Stylianos E Antonarakis
[show abstract]
[hide abstract]
ABSTRACT: Natural variation in DNA sequence contributes to individual differences in quantitative traits. While multiple studies have shown genetic control over gene expression variation, few additional cellular traits have been investigated. Here, we investigated the natural variation of NADPH oxidase-dependent hydrogen peroxide (H(2)O(2) release), which is the joint effect of reactive oxygen species (ROS) production, superoxide metabolism and degradation, and is related to a number of human disorders. We assessed the normal variation of H(2)O(2) release in lymphoblastoid cell lines (LCL) in a family-based 3-generation cohort (CEPH-HapMap), and in 3 population-based cohorts (KORA, GenCord, HapMap). Substantial individual variation was observed, 45% of which were associated with heritability in the CEPH-HapMap cohort. We identified 2 genome-wide significant loci of Hsa12 and Hsa15 in genome-wide linkage analysis. Next, we performed genome-wide association study (GWAS) for the combined KORA-GenCord cohorts (n = 279) using enhanced marker resolution by imputation (>1.4 million SNPs). We found 5 significant associations (p<5.00×10-8) and 54 suggestive associations (p<1.00×10-5), one of which confirmed the linked region on Hsa15. To replicate our findings, we performed GWAS using 58 HapMap individuals and ∼2.1 million SNPs. We identified 40 genome-wide significant and 302 suggestive SNPs, and confirmed genome signals on Hsa1, Hsa12, and Hsa15. Genetic loci within 900 kb from the known candidate gene p67phox on Hsa1 were identified in GWAS in both cohorts. We did not find replication of SNPs across all cohorts, but replication within the same genomic region. Finally, a highly significant decrease in H(2)O(2) release was observed in Down Syndrome (DS) individuals (p<2.88×10-12). Taken together, our results show strong evidence of genetic control of H(2)O(2) in LCL of healthy and DS cohorts and suggest that cellular phenotypes, which themselves are also complex, may be used as proxies for dissection of complex disorders.
PLoS ONE 01/2012; 7(8):e43566. · 4.09 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: In mammals, the NADPH oxidase family of enzymes comprises seven members: NOXs 1-5, DUOX1, and DUOX2. All of these enzymes function to move an electron across cellular membranes, transferring it to oxygen to generate the superoxide anion. This generation of reactive oxygen species has important physiological and pathophysiological roles. NOX5 is perhaps the least well understood of these NOX isoforms, in part because the gene is not present in mice or rats. In recent years, however, there has been a rapid increase in our understanding of the NOX5 gene, the structural and biochemical aspects of the NOX5 enzyme, the role NOX5 plays in health and disease, and the development of novel NOX inhibitors. This review takes a look back at some historical aspects of the discovery of NOX5 and summarizes our current understanding of the enzyme.
Free radical biology & medicine 12/2011; 52(4):725-34. · 5.42 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The relative weight of various etiologies of dementia as predictors of long-term mortality after other risk factors have been taken into account remains unclear. We investigated the 5-year mortality risk associated with dementia in elderly people after discharge from acute care, taking into account comorbid conditions and functionality.
A prospective cohort study of 444 patients (mean age: 85 years; 74% female) discharged from the acute geriatric unit of Geneva University Hospitals. On admission, each subject underwent a standardized diagnostic evaluation: demographic variables, cognitive, comorbid medical conditions and functional assessment. Patients were followed yearly by the same team. Predictors of survival at 5 years were evaluated by Cox proportional hazards models.
The univariate model showed that being older and male, and having vascular and severe dementia, comorbidity and functional disability, were predictive of shorter survival. However, in the full multivariate model adjusted for age and sex, the effect of dementia type or severity completely disappeared when all the variables were added. In multivariate analysis, the best predictor was higher comorbidity score, followed by functional status (R(2) = 23%).
The identification of comorbidity and functional impairment effects as predictive factors for long-term mortality independent of cognitive status may increase the accuracy of long-term discharge planning.
Dementia and Geriatric Cognitive Disorders 09/2011; 32(2):103-10. · 2.14 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Stem cell transplantation consists in the introduction of stem cells or derived products in a diseased organism. Because of the differentiation properties of stem cells, the goal is to replace damaged cells or tissues. Numbers of stem cell were identified and isolated from embryos, fetuses, or adult organs, harboring different properties, and thus providing multiple strategies of regenerative medicine for different diseases. More recently, the artificial induction of stemness properties in adult somatic cells has proposed a new way to generate stem cells. One important concern of stem cell therapy is the possible risk that transplanted stem cells could be rejected by the recipient's immune system. Depending on their source, stem cell transplantation is associated with diverse immunological situations. If some sources allow autologous transplantation, others cannot bypass an allogeneic context between the donor and the recipient. This review summarizes all of the stem cell sources for regenerative medicine and the immunological questions associated to their use. Regarding the emerging strategies compatible with autologous transplantation, this article points notably the complexity of the choice between the immunological safety and the specific advantages of allogeneic stem cells.
Seminars in Immunopathology 05/2011; 33(6):519-24. · 6.27 Impact Factor
-
The Journal of allergy and clinical immunology 05/2011; 128(3):675-7. · 9.17 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Embryonic stem cells (ESC), derived from the early inner cell mass (ICM), are constituted of theoretically homogeneous pluripotent cells. Our study was designed to test this concept using experimental approaches that allowed characterization of progenies derived from single parental mouse ESC. Flow cytometry analysis showed that a fraction of ESC submitted to neural differentiation generates progenies that escape the desired phenotype. Live imaging of individual cells demonstrated significant variations in the capacity of parental ESC to generate neurons, raising the possibility of clonal diversity among ESC. To further substantiate this hypothesis, clonal sublines from ESC were generated by limit dilution. Transcriptome analysis of undifferentiated sublines showed marked differences in gene expression despite the fact that all clones expressed pluripotency markers. Sublines showed distinct differentiation potential, both in phenotypic differentiation assays and with respect to gene expression in embryoid bodies. Clones generated from another ESC line also showed individualities in their differentiation potential, demonstrating the wider applicability of these findings. Taken together, our observations demonstrate that pluripotent ESC consist of individual cell types with distinct differentiation potentials. These findings identify novel elements for the biological understanding of ESC and provide new tools with a major potential for their future in vitro and in vivo use.
Journal of Cellular and Molecular Medicine 05/2011; 16(3):456-67. · 4.13 Impact Factor
-
Vincent Jaquet,
Julien Marcoux,
Eric Forest,
Kevin G Leidal,
Sally McCormick,
Yvonne Westermaier,
Remo Perozzo,
Olivier Plastre,
Laetitia Fioraso-Cartier,
Becky Diebold,
Leonardo Scapozza,
William M Nauseef,
Franck Fieschi, Karl-Heinz Krause,
Karen Bedard
[show abstract]
[hide abstract]
ABSTRACT: Celastrol is one of several bioactive compounds extracted from the medicinal plant Tripterygium wilfordii. Celastrol is used to treat inflammatory conditions, and shows benefits in models of neurodegenerative disease, cancer and arthritis, although its mechanism of action is incompletely understood.
Celastrol was tested on human NADPH oxidases (NOXs) using a panel of experiments: production of reactive oxygen species and oxygen consumption by NOX enzymes, xanthine oxidase activity, cell toxicity, phagocyte oxidase subunit translocation, and binding to cytosolic subunits of NOX enzymes. The effect of celastrol was compared with diphenyleneiodonium, an established inhibitor of flavoproteins.
Low concentrations of celastrol completely inhibited NOX1, NOX2, NOX4 and NOX5 within minutes with concentration-response curves exhibiting higher Hill coefficients and lower IC₅₀ values for NOX1 and NOX2 compared with NOX4 and NOX5, suggesting differences in their mode of action. In a cell-free system, celastrol had an IC₅₀ of 1.24 and 8.4 µM for NOX2 and NOX5, respectively. Cytotoxicity, oxidant scavenging, and inhibition of p47(phox) translocation could not account for NOX inhibition. Celastrol bound to a recombinant p47(phox) and disrupted the binding of the proline rich region of p22(phox) to the tandem SH3 domain of p47(phox) and NOXO1, the cytosolic subunits of NOX2 and NOX1, respectively.
These results demonstrate that celastrol is a potent inhibitor of NOX enzymes in general with increased potency against NOX1 and NOX2. Furthermore, inhibition of NOX1 and NOX2 was mediated via a novel mode of action, namely inhibition of a functional association between cytosolic subunits and the membrane flavocytochrome.
British Journal of Pharmacology 04/2011; 164(2b):507-20. · 4.41 Impact Factor
-
Stephanie Carnesecchi,
Christine Deffert,
Yves Donati,
Olivier Basset,
Boris Hinz,
Olivier Preynat-Seauve,
Cecile Guichard,
Jack L Arbiser,
Botond Banfi,
Jean-Claude Pache,
Constance Barazzone-Argiroffo, Karl-Heinz Krause
[show abstract]
[hide abstract]
ABSTRACT: The pathogenesis of pulmonary fibrosis is linked to oxidative stress, possibly generated by the reactive oxygen species (ROS) generating NADPH oxidase NOX4. Epithelial cell death is a crucial early step in the development of the disease, followed only later by the fibrotic stage. We demonstrate that in lungs of patients with idiopathic lung fibrosis, there is strong expression of NOX4 in hyperplastic alveolar type II cells.
To study a possible causative role of NOX4 in the death of alveolar cells, we have generated NOX4-deficient mice.
Three weeks after administration of bleomycin, wild-type (WT) mice developed massive fibrosis, whereas NOX4-deficient mice displayed almost normal lung histology, and only little Smad2 phosphorylation and accumulation of myofibroblasts. However, the protective effects of NOX4 deficiency preceded the fibrotic stage. Indeed, at day 7 after bleomycin, lungs of WT mice showed massive increase in epithelial cell apoptosis and inflammation. In NOX4-deficient mice, no increase in apoptosis was observed, whereas inflammation was comparable to WT. In vitro, NOX4-deficient primary alveolar epithelial cells exposed to transforming growth factor-β(1) did not generate ROS and were protected from apoptosis. Acute treatment with the NOX inhibitors also blunted transforming growth factor-β(1)-induced apoptosis.
ROS generation by NOX4 is a key player in epithelial cell death leading to pulmonary fibrosis.
Antioxidants & Redox Signaling 03/2011; 15(3):607-19. · 8.20 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The expression and the role of the chemokine receptor CCR5 have been mainly studied in the context of HIV infection. However, this protein is also expressed in the brain, where it can be crucial in determining the outcome in response to different insults. CCR5 expression can be deleterious or protective in controlling the progression of certain infections in the CNS, but it is also emerging that it could play a role in non-infectious diseases. In particular, it appears that, in addition to modulating immune responses, CCR5 can influence neuronal survival. Here, we summarize the present knowledge about the expression of CCR5 in the brain and highlight recent findings suggesting its possible involvement in neuroprotective mechanisms.
Progress in Neurobiology 02/2011; 93(2):297-311. · 8.87 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The relative weight of various etiologies of dementia and mild cognitive impairment (MCI) as predictors of intra-hospital, short- and long-term mortality in very old acutely ill patients suffering from multiple comorbid conditions remains unclear. We investigated intra-hospital, 1- and 5-year mortality risk associated with dementia and its various etiologies in a very old population after discharge from acute care.
Prospective cohort study of 444 patients (mean age 85 years; 74% female) discharged from the acute geriatric unit of Geneva University Hospital. On admission, each subject underwent standardized evaluation of cognitive and comorbid conditions. Patients were followed yearly by the same team. Predictive variables were age, sex, cognitive diagnosis, dementia etiology and severity. Survival during hospitalization, at 1- and 5-year follow-ups was the outcome of interest evaluated with Cox proportional hazard models.
Two hundred and six patients were cognitively normal, 48 had MCI, and 190 had dementia: of these, there were 75 cases of Alzheimer's disease (AD), 20 of vascular dementia (VaD), 82 of mixed dementia (MD) and 13 of other types of dementia. The groups compared were statistically similar in age, sex, education level and comorbidity score. After 5 years of follow-up, 60% of the patients had died. Regarding intra-hospital mortality, none of the predictive variables was associated with mortality. MCI, AD and MD were not predictive of short- or long-term mortality. Features significantly associated with reduced survival at 1 and 5 years were being older, male, and having vascular or severe dementia. When all the variables were added in the multiple model, the dementia effect completely disappeared.
Dementia (all etiologies) is not predictive of mortality. The observed VaD effect is probably linked to cardiovascular risk comorbidities: hypertension, stroke and hyperlipidemia.
Aging clinical and experimental research 02/2011; 23(1):60-6. · 1.55 Impact Factor
-
Nature medicine 01/2011; 17(1):31-2; author reply 32-3. · 27.14 Impact Factor
-
Sarah Garrido-Urbani,
Stephane Jemelin,
Christine Deffert,
Stéphanie Carnesecchi,
Olivier Basset,
Cédric Szyndralewiez,
Freddy Heitz,
Patrick Page,
Xavier Montet,
Liliane Michalik,
Jack Arbiser,
Curzio Rüegg, Karl Heinz Krause,
Beat A Imhof,
Beat Imhof
[show abstract]
[hide abstract]
ABSTRACT: Reactive oxygen species, ROS, are regulators of endothelial cell migration, proliferation and survival, events critically involved in angiogenesis. Different isoforms of ROS-generating NOX enzymes are expressed in the vasculature and provide distinct signaling cues through differential localization and activation. We show that mice deficient in NOX1, but not NOX2 or NOX4, have impaired angiogenesis. NOX1 expression and activity is increased in primary mouse and human endothelial cells upon angiogenic stimulation. NOX1 silencing decreases endothelial cell migration and tube-like structure formation, through the inhibition of PPARα, a regulator of NF-κB. Administration of a novel NOX-specific inhibitor reduced angiogenesis and tumor growth in vivo in a PPARα dependent manner. In conclusion, vascular NOX1 is a critical mediator of angiogenesis and an attractive target for anti-angiogenic therapies.
PLoS ONE 01/2011; 6(2):e14665. · 4.09 Impact Factor
