Regulation of ROS signal transduction by NADPH oxidase 4 localization. J Cell Biol

Department of Medicine, Division of Cardiovascular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
The Journal of Cell Biology (Impact Factor: 9.69). 07/2008; 181(7):1129-39. DOI: 10.1083/jcb.200709049
Source: PubMed

ABSTRACT Reactive oxygen species (ROS) function as intracellular signaling molecules in a diverse range of biological processes. However, it is unclear how freely diffusible ROS dictate specific cellular responses. In this study, we demonstrate that nicotinamide adenine dinucleotide phosphate reduced oxidase 4 (Nox4), a major Nox isoform expressed in nonphagocytic cells, including vascular endothelium, is localized to the endoplasmic reticulum (ER). ER localization of Nox4 is critical for the regulation of protein tyrosine phosphatase (PTP) 1B, also an ER resident, through redox-mediated signaling. Nox4-mediated oxidation and inactivation of PTP1B in the ER serves as a regulatory switch for epidermal growth factor (EGF) receptor trafficking and specifically acts to terminate EGF signaling. Consistent with this notion, PTP1B oxidation could also be modulated by ER targeting of antioxidant enzymes but not their untargeted counterparts. These data indicate that the specificity of intracellular ROS-mediated signal transduction may be modulated by the localization of Nox isoforms within specific subcellular compartments.

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    • "Unlike the majority of Nox proteins, which produce superoxide, Nox4 appears to primarily produce hydrogen peroxide (H 2 O 2 ) [26] [27] [28]. In response to physiological stimuli, Nox4 generates H 2 O 2 and activates signaling pathways, such as insulin [29] and epidermal growth factor signaling [30], through the oxidation of specific protein thiols. Protein thiols can undergo oxidation to various oxidation products, including S-glutathionylated thiols, i.e., mixed disulfide bonds between protein thiols and glutathione [31]. "
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    ABSTRACT: Aims Dietary supplementation with ursolic acid (UA) prevents monocyte dysfunction in diabetic mice and protects mice against atherosclerosis and loss of renal function. The goal of this study was to determine the molecular mechanism by which UA prevents monocyte dysfunction induced by metabolic stress. Methods and Results Metabolic stress sensitizes or “primes” human THP-1 monocytes and murine peritoneal macrophages to the chemoattractant MCP-1, converting these cells into a hyper-chemotactic phenotype. UA protected THP-1 monocytes and peritoneal macrophages against metabolic priming and prevented their hyper-reactivity to MCP-1. UA blocked the metabolic stress-induced increase in global protein-S-glutathionylation, a measure of cellular thiol oxidative stress, and normalized actin-S-glutathionylation. UA also restored MAPK phosphatase-1 (MKP1) protein expression and phosphatase activity, decreased by metabolic priming, and normalized p38 MAPK activation. Neither metabolic stress nor UA supplementation altered mRNA or protein levels of glutaredoxin-1, the principal enzyme responsible for the reduction of mixed disulfides between glutathione and protein thiols in these cells. However, the induction of Nox4 by metabolic stress, required for metabolic priming, was inhibited by UA in both THP-1 monocytes and peritoneal macrophages. Conclusion UA protects THP-1 monocytes against dysfunction by suppressing metabolic stress-induced Nox4 expression, thereby preventing the Nox4-dependent dysregulation of redox-sensitive processes, including actin turnover and MAPK-signaling, two key processes that control monocyte migration and adhesion. This study provides a novel mechanism for the anti-inflammatory and athero- and renoprotective properties of UA and suggests that dysfunctional blood monocytes may be primary targets of UA and related compounds.
    01/2014; 2. DOI:10.1016/j.redox.2014.01.003
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    • "It becomes clear that ROS production is largely dependent on the subcellular location, possibly due to different sets and concentrations of molecular intermediates at these regions [8] [36] [37]. In this study, we designed a new FRET-based ROS-paxillin sensor capable of monitoring ROS production at FA sites. "
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    ABSTRACT: Reactive oxygen species (ROS) have been shown to play crucial roles in regulating various cellular functions, e.g. focal adhesion (FA) dynamics and cell migration upon growth factor stimulation. However, it is not clear how ROS are regulated at subcellular FA sites to impact cell migration. We have developed a biosensor capable of monitoring ROS production at FA sites in live cells with high sensitivity and specificity, utilizing fluorescence resonance energy transfer (FRET). The results revealed that platelet derived growth factor (PDGF) can induce ROS production at FA sites, which is mediated by Rac1 activation. In contrast, integrins, specifically integrin αvβ3, inhibits this local ROS production. The RhoA activity can mediate this inhibitory role of integrins in regulating ROS production. Therefore, PDGF and integrin αvβ3 coordinate to have an antagonistic effect in the ROS production at FA sites to regulate cell adhesion and migration.
    Biomaterials 02/2013; 34(15). DOI:10.1016/j.biomaterials.2013.01.092 · 8.31 Impact Factor
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    • "Other Nox homologues are also expressed in the arterial wall, with the dominant subtypes found in large arteries being Nox2 and Nox4 in the endothelium and Nox1 and Nox4 in smooth muscle (Brandes and Schroder, 2008; Lassègue and Griendling, 2010). In contrast to Nox2, the Nox4 homologue is constitutively active, localizes to the endoplasmic/sarcoplasmic reticulum, generates H 2 O 2 in preference to O 2 @BULLET− , and is insensitive to apocynin because catalytic activity depends on Nox4/p22phox without the requirement for p47phox and other proteins that characterizes the phagocytic complex (Brandes and Schroder, 2008; Chen et al., 2008; Dikalov et al., 2008; Ray et al., 2011). "
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    ABSTRACT: Chronic arsenic ingestion predisposes to vascular disease, but underlying mechanisms are poorly understood. In the present study we have analyzed the effects of short-term arsenite exposure on vascular function and endothelium-dependent relaxation. Endothelium-dependent relaxations, nitric oxide (NO) and endothelium derived hyperpolarizing factor (EDHF)-type, were studied in rabbit iliac artery and aortic rings using the G protein-coupled receptor agonist acetylcholine (ACh) and by cyclopiazonic acid (CPA), which promotes store-operated Ca2+ entry by inhibiting the endothelial SERCA pump. Production of reactive oxygen species (ROS) in the endothelium of rabbit aortic valve leaflets and endothelium-denuded RIA and aortic rings was assessed by imaging of dihydroethidium. In the iliac artery, exposure to 100 μM arsenite for 30 min potentiated EDHF-type relaxations evoked by both CPA and ACh. Potentiation was prevented by catalase, the catalase/superoxide dismutase mimetic manganese porphyrin and the NADPH oxidase inhibitor apocynin. By contrast in aortic rings, that exhibited negligible EDHF-type responses, endothelium-dependent NO-mediated relaxations evoked by CPA and ACh were unaffected by arsenite. Arsenite induced apocynin-sensitive increases in ROS production in the aortic valve endothelium, but not in the media and adventitia of the iliac artery and aorta. Our results suggest that arsenite can potentiate EDHF-type relaxations via a mechanism that is dependent on hydrogen peroxide, thus demonstrating that dismutation of the superoxide anion generated by NADPH oxidase can potentially offset loss of NO bioavailability under conditions of reduced eNOS activity. By contrast, selective increases in endothelial ROS production following exposure to arsenite failed to modify relaxations mediated by endogenous NO.
    Toxicology 02/2013; 306(100). DOI:10.1016/j.tox.2013.01.019 · 3.75 Impact Factor
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