Downstream Targets and Intracellular Compartmentalization in Nox Signaling

Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School Worcester, Massachusetts 01605, USA.
Antioxidants & Redox Signaling (Impact Factor: 7.41). 04/2009; 11(10):2467-80. DOI: 10.1089/ARS.2009.2594
Source: PubMed


Reactive oxygen species (ROS) have become recognized for their role as second messengers in a multitude of physiologic responses. Emerging evidence points to the importance of the NADPH oxidase family of ROS-producing enzymes in mediating redox-sensitive signal transduction. However, a clear paradox exists between the specificity required for signaling and the nature of ROS as both diffusible and highly reactive molecules. We seek to understand the targets and compartmentalization of the NADPH oxidase signaling to determine how NADPH oxidase-derived ROS fit into established signaling paradigms. Herein we review recent data that link cellular NADPH oxidase enzymes to ROS signaling, with a particular focus on the mechanism(s) involved in achieving signaling specificity.

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Available from: Siobhan M Craige, Aug 11, 2015
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    • "The NOX family of NADPH oxidase enzymes are membrane-bound electron carriers, which use NADPH as electron donor and oxygen as acceptor. NADPH oxidases localize to cellular membrane compartments via targeting proteins, facilitating hydrogen peroxide (H 2 O 2 ) production within spatially confined areas [31] [35]. There are various molecular mechanisms within a cell designed to counteract overproduction of ROS. "
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    ABSTRACT: Oxidative stress damages multiple cellular components including DNA, lipids, and proteins and has been linked to pathological alterations in nonalcoholic fatty liver disease (NAFLD). Reactive oxygen species (ROS) emission, resulting from nutrient overload and mitochondrial dysfunction, is thought to be a principal mediator in NAFLD progression, particularly toward the development of hepatic insulin resistance. In the context of insulin signalling, ROS has a dual role, as both a facilitator and inhibitor of the insulin signalling cascade. ROS mediate these effects through redox modifications of cysteine residues affecting phosphatase enzyme activity, stress-sensitive kinases, and metabolic sensors. This review highlights the intricate relationship between redox-sensitive proteins and insulin signalling in the context of fatty liver disease, and to a larger extent, the importance of reactive oxygen species as primary signalling molecules in metabolically active cells.
    International Journal of Cell Biology 02/2014; 2014(1):519153. DOI:10.1155/2014/519153
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    • "However , in non-innate immune cells, ROS are more often associated with oxidative stress, as chronic imbalance in the cellular reduction–oxidation (redox) state is implicated in various diseases, including vascular thrombosis [1] [2]. ROS also represent important secondary messengers in signal transduction cascades through their ability to oxidatively modify protein thiols, such as catalytic cysteinyl residues in protein tyrosine phosphatases, or interact with other reactive compounds [3] [4]. As activated platelets produce predominantly intracellular ROS; platelet-derived ROS are believed to have a role in regulating cellular function rather than providing a physiological response to pathogen invasion [5] [6]. "
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    ABSTRACT: Activation of the platelet-specific collagen receptor, glycoprotein (GP) VI, induces intracellular reactive oxygen species (ROS) production; however the relevance of ROS to GPVI-mediated platelet responses remains unclear. The objective of this study was to explore the role of the ROS-producing NADPH oxidase (Nox)1 and 2 complexes in GPVI-dependent platelet activation and collagen-induced thrombus formation. ROS production was measured by quantitating changes in the oxidation-sensitive dye, H2DCF-DA, following platelet activation with the GPVI-specific agonist, collagen related peptide (CRP). Using a pharmacological inhibitor specific for Nox1, 2-acetylphenothiazine (ML171), and Nox2 deficient mice, we show that Nox1 is the key Nox homolog regulating GPVI-dependent ROS production. Nox1, but not Nox2, was essential for CRP-dependent thromboxane (Tx)A2 production, which was mediated in part through p38 MAPK signaling; while neither Nox1 nor Nox2 was significantly involved in regulating CRP-induced platelet aggregation/integrin αIIbβ3 activation, platelet spreading, or dense granule and α-granule release (ATP release and P-selectin surface expression, respectively). Ex-vivo perfusion analysis of mouse whole blood revealed that both Nox1 and Nox2 were involved in collagen-mediated thrombus formation at arterial shear. Together these results demonstrate a novel role for Nox1 in regulating GPVI-induced ROS production, which is essential for optimal p38 activation and subsequent TxA2 production, providing an explanation for reduced thrombus formation following Nox1 inhibition.
    01/2014; 2(1):178-86. DOI:10.1016/j.redox.2013.12.023
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    • "The original member of the Nox family is the phagocytic Nox gp91phox or Nox2, which has been studied extensively for its role in the respiratory burst of neutrophils and macrophages [9], [10]. Since the discovery of Nox2, several additional Nox family members have been identified and shown to be involved in redox-sensitive signaling pathways [7], [11], [12], [13]. We identified Nox4 in monocytes and macrophages as a source of intracellular ROS involved in macrophage death [14]. "
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    ABSTRACT: We showed that metabolic disorders promote thiol oxidative stress in monocytes, priming monocytes for accelerated chemokine-induced recruitment, and accumulation at sites of vascular injury and the progression of atherosclerosis. The aim of this study was to identify both the source of reactive oxygen species (ROS) responsible for thiol oxidation in primed and dysfunctional monocytes and the molecular mechanisms through which ROS accelerate the migration and recruitment of monocyte-derived macrophages. We found that Nox4, a recently identified NADPH oxidase in monocytes and macrophages, localized to focal adhesions and the actin cytoskeleton, and associated with phospho-FAK, paxillin, and actin, implicating Nox4 in the regulation of monocyte adhesion and migration. We also identified Nox4 as a new, metabolic stress-inducible source of ROS that controls actin S-glutathionylation and turnover in monocytes and macrophages, providing a novel mechanistic link between Nox4-derived H2O2 and monocyte adhesion and migration. Actin associated with Nox4 was S-glutathionylated, and Nox4 association with actin was enhanced in metabolically-stressed monocytes. Metabolic stress induced Nox4 and accelerated monocyte adhesion and chemotaxis in a Nox4-dependent mechanism. In conclusion, our data suggest that monocytic Nox4 is a central regulator of actin dynamics, and induction of Nox4 is the rate-limiting step in metabolic stress-induced monocyte priming and dysfunction associated with accelerated atherosclerosis and the progression of atherosclerotic plaques.
    PLoS ONE 06/2013; 8(6):e66964. DOI:10.1371/journal.pone.0066964 · 3.23 Impact Factor
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