NADPH oxidase Nox1 contributes to ischemic injury in experimental stroke in mice

Kahles, Timo; Kohnen, Andreas; Heumueller, Sabine; Rappert, Angelika; Bechmann, Ingo; Liebner, Stefan; Wittko, Ina M.; Neumann‐Haefelin, Tobias; Steinmetz, Helmuth; Schröeder, Katrin; Brandes, Ralf P.

doi:10.1016/j.nbd.2010.05.023

Cited by 81 publications

(66 citation statements)

References 35 publications

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“…Still other studies have shown that NOX1 may exert a protective effect in stroke (129). NOX1-deficient mice showed no difference in sub-cortical cerebral infarct volume, but a four-fold greater cortical infarct volume.…”

Section: Ischemic Conditionsmentioning

confidence: 82%

NOX2 As a Target for Drug Development: Indications, Possible Complications, and Progress

Diebold

Smith

Yang

et al. 2015

Antioxidants & Redox Signaling

106

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Significance: NOX2 is important for host defense, and yet is implicated in a large number of diseases in which inflammation plays a role in pathogenesis. These include acute and chronic lung inflammatory diseases, stroke, traumatic brain injury, and neurodegenerative diseases, including Alzheimer's and Parkinson's Diseases. Recent Advances: Recent drug development programs have targeted several NOX isoforms that are implicated in a variety of diseases. The focus has been primarily on NOX4 and NOX1 rather than on NOX2, due, in part, to concerns about possible immunosuppressive side effects. Nevertheless, NOX2 clearly contributes to the pathogenesis of many inflammatory diseases, and its inhibition is predicted to provide a novel therapeutic approach. Critical Issues: Possible side effects that might arise from targeting NOX2 are discussed, including the possibility that such inhibition will contribute to increased infections and/or autoimmune disorders. The state of the field with regard to existing NOX2 inhibitors and targeted development of novel inhibitors is also summarized. Future Directions: NOX2 inhibitors show particular promise for the treatment of inflammatory diseases, both acute and chronic. Theoretical side effects include pro-inflammatory and autoimmune complications and should be considered in any therapeutic program, but in our opinion, available data do not indicate that they are sufficiently likely to eliminate NOX2 as a drug target, particularly when weighed against the seriousness of many NOX2-related indications. Model studies demonstrating efficacy with minimal side effects are needed to encourage future development of NOX2 inhibitors as therapeutic agents. Antioxid. Redox Signal. 23,

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Section: Ischemic Conditionsmentioning

confidence: 82%

NOX2 As a Target for Drug Development: Indications, Possible Complications, and Progress

Diebold

Smith

Yang

et al. 2015

Antioxidants & Redox Signaling

106

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“…Previous studies suggested that activation of both platelets and leukocytes needs to be controlled to treat thromboinflammatory conditions such as hepatic and cerebral ischemia/reperfusion injury 28,29,[34][35][36] and that inhibition or deletion of GPIba and aMb2 integrin, but not aIIbb3, protects mice following ischemia/reperfusion injury in a middle cerebral artery. 34,36,37 Although there are some reports showing the role of NOX1 and NOX4 in stroke, 38,39 several studies using pharmacologic and genetic approaches demonstrated that NOX2 is crucial for the pathogenesis of ischemic stroke 40,41 and that hematopoietic cell NOX2 contributes more to the development of stroke than endothelial or brain resident cell NOX2. 42 Because neutrophilplatelet interactions are important for vascular occlusion under thromboinflammatory conditions 1 and because intravascular cell NOX2 regulates neutrophil-platelet interactions during vascular inflammation (Figures 1 and 2), our findings in part explain how NOX2 KO mice show protective effects in ischemic stroke.…”

Section: Discussionmentioning

confidence: 99%

NOX2 is critical for heterotypic neutrophil-platelet interactions during vascular inflammation

Kim¹,

Li²,

Tseng

et al. 2015

Blood

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Key Points• NOX2-generated ROS regulate the function of surface receptors required for platelet-neutrophil interactions during vascular inflammation.Platelet-leukocyte interactions on activated endothelial cells play an important role during microvascular occlusion under oxidative stress conditions. However, it remains poorly understood how neutrophil-platelet interactions are regulated during vascular inflammation. By using intravital microscopy with mice lacking nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) and their bone marrow chimera, we demonstrated that NOX2 from both hematopoietic and endothelial cells is crucial for neutrophil-platelet interactions during tumor necrosis factor alpha-induced venular inflammation. Platelet NOX2-produced reactive oxygen species (ROS) regulated P-selectin exposure upon agonist stimulation and the ligand-binding function of glycoprotein Iba. Furthermore, neutrophil NOX2-generated ROS enhanced the activation and ligand-binding activity of aMb2 integrin following N-formyl-methionyl-leucyl phenylalanine stimulation. Studies with isolated cells and a mouse model of hepatic ischemia/reperfusion injury revealed that NOX2 from both platelets and neutrophils is required for cell-cell interactions, which contribute to the pathology of hepatic ischemia/reperfusion injury. Platelet NOX2 modulated intracellular Ca 21 release but not store-operated Ca 21 entry (SOCE), whereas neutrophil NOX2 was crucial for SOCE but not intracellular Ca 21 release. Different regulation of Ca 21 signaling by platelet and neutrophil NOX2 correlated with differences in the phosphorylation of AKT, ERK, and p38MAPK. Our results indicate that platelet and neutrophil NOX2-produced ROS are critical for the function of surface receptors essential for neutrophil-platelet interactions during vascular inflammation. (Blood. 2015;126(16):1952-1964

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“…However, after a subgroup analysis, the authors postulated that cortical strokes were four times increased in NOX1 KO versus control mice, possibly indicating that NOX1 may play a protective role by limiting cortical damage. Another group reported opposite findings, that is, reduced infarct size in NOX1 KO mice (31). This effect was only visible when the ischemic period lasted 1 h but not when lasting longer.…”

Section: No Implication Of Nox1mentioning

confidence: 96%

“…With regard to a possible role of NOX1 in stroke, three studies have been published that all used the same NOX1 KO mouse strain (30,31,33), although not all studies reported details according to the STAIR criteria. Jackman et al concluded that NOX1 is relevant for angiotensin-stimulated ROS production but has no impact on overall ROS production, stroke size, and neurological outcome (30).…”

Section: No Implication Of Nox1mentioning

confidence: 99%

Neuroprotection After Stroke by Targeting NOX4 As a Source of Oxidative Stress

Radermacher

Wingler

Langhauser

et al. 2013

Antioxidants & Redox Signaling

127

107

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Significance: Stroke, a leading cause of death and disability, poses a substantial burden for patients, relatives, and our healthcare systems. Only one drug is approved for treating stroke, and more than 30 contraindications exclude its use in 90% of all patients. Thus, new treatments are urgently needed. In this review, we discuss oxidative stress as a pathomechanism of poststroke neurodegeneration and the inhibition of its source, type 4 nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX4), as a conceptual breakthrough in stroke therapy. Recent Advances: Among potential sources of reactive oxygen species (ROS), the NOXes stand out as the only enzyme family that is solely dedicated to forming ROS. In rodents, three cerebrovascular NOXes exist: the superoxide-forming NOX1 and 2 and the hydrogen peroxide-forming NOX4. Studies using NOX1 knockout mice gave conflicting results, which overall do not point to a role for this isoform. Several reports find NOX2 to be relevant in stroke, albeit to variable and moderate degrees. In our hands, NOX4 is, by far, the major source of oxidative stress and neurodegeneration on ischemic stroke. Critical Issues: We critically discuss the tools that have been used to validate the roles of NOX in stroke. We also highlight the relevance of different animal models and the need for advanced quality control in preclinical stroke research. Future Directions: The development of isoform-specific NOX inhibitors presents a precious tool for further clarifying the role and drugability of NOX homologues. This could pave the avenue for the first clinically effective neuroprotectant applied poststroke, and even beyond this, stroke could provide a proof of principle for antioxidative stress therapy.

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NADPH oxidase Nox1 contributes to ischemic injury in experimental stroke in mice

Cited by 81 publications

References 35 publications

NOX2 As a Target for Drug Development: Indications, Possible Complications, and Progress

NOX2 As a Target for Drug Development: Indications, Possible Complications, and Progress

NOX2 is critical for heterotypic neutrophil-platelet interactions during vascular inflammation

Neuroprotection After Stroke by Targeting NOX4 As a Source of Oxidative Stress

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