NADPH Oxidase, NOX1, Mediates Vascular Injury in Ischemic Retinopathy

Wilkinson-Berka, Jennifer L.; Deliyanti, Devy; Rana, Indrajeetsinh; Miller, Antonia Grace; Agrotis, Alexander; Armani, Roksana; Szyndralewiez, Cédric; Wingler, Kirstin; Touyz, Rhian M.; Cooper, Mark E.; Jandeleit‐Dahm, Karin; Schmidt, Harald

doi:10.1089/ars.2013.5357

Cited by 109 publications

(128 citation statements)

References 57 publications

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“…Renal Nox4 gene expression was significantly reduced with both doses of GKT137831 and this may reflect reduced renal injury. Similar effects were recently reported in microglial and Müller cells exposed to hypoxia and treated with GKT137831 [32]. It is therefore possible that reduced expression and enzyme activity both contribute to the pharmacological effects of NOX inhibitors.…”

Section: Discussionsupporting

confidence: 84%

“…Taken together, the available data suggest that selective inhibition of NOX1 may be particularly effective to specifically prevent diabetes-induced vascular disease in conduit arteries and the retina [32]. NOX inhibitors with a broader selectivity profile, including NOX1, NOX4 and, possibly, NOX5 may represent more attractive therapeutic options in patients with associated kidney disease.…”

Section: Discussionmentioning

confidence: 96%

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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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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 96%

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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“…Knockout mice and inhibition studies strongly suggested NOX1 (green lines) as a therapeutic target in diabetic atherosclerosis (64), ischemic retinopathy (179), and-in interaction with NOX4-liver fibrosis (5,79,129). A role in melanoma progression and tumor angiogenesis (54) needs to be confirmed in NOX1 knockout mice, while a role of NOX1 in heart I/R injury (21) needs to be confirmed by pharmacologic inhibition of NOX1.…”

Section: Fig 7 Nox Enzymes As Validated Therapeutic Targetsmentioning

confidence: 99%

“…The first showed decreased lesion area and macrophage infiltration, two hallmarks of atherosclerosis, in NOX1/ApoE double KO mice after high fat diet feeding compared with ApoE KO mice (160); the second showed decreased atherosclerotic lesions and cellular surface adhesion factor CD44 in ApoE KO mice treated with GKT136901 (176). Very recently, NOX1 was also validated as a therapeutic target in ischemic retinopathy (179). Using a rodent model of retinopathy of prematurity, which is a major cause of blindness caused by damage to the retinal microvasculature, retinas of NOX1 KO mice showed reduced signs of retinopathy, such as neovascularization and avascular retina.…”

Section: Fig 7 Nox Enzymes As Validated Therapeutic Targetsmentioning

confidence: 99%

Evolution of NADPH Oxidase Inhibitors: Selectivity and Mechanisms for Target Engagement

Altenhöfer

Radermacher

Kleikers

et al. 2015

Antioxidants & Redox Signaling

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Significance: Oxidative stress, an excess of reactive oxygen species (ROS) production versus consumption, may be involved in the pathogenesis of different diseases. The only known enzymes solely dedicated to ROS generation are nicotinamide adenine dinucleotide phosphate (NADPH) oxidases with their catalytic subunits (NOX). After the clinical failure of most antioxidant trials, NOX inhibitors are the most promising therapeutic option for diseases associated with oxidative stress. Recent Advances: Historical NADPH oxidase inhibitors, apocynin and diphenylene iodonium, are un-specific and not isoform selective. Novel NOX inhibitors stemming from rational drug discovery approaches, for example, GKT137831, ML171, and VAS2870, show improved specificity for NADPH oxidases and moderate NOX isoform selectivity. Along with NOX2 docking sequence (NOX2ds)-tat, a peptide-based inhibitor, the use of these novel small molecules in animal models has provided preliminary in vivo evidence for a pathophysiological role of specific NOX isoforms. Critical Issues: Here, we discuss whether novel NOX inhibitors enable reliable validation of NOX isoforms' pathological roles and whether this knowledge supports translation into pharmacological applications. Modern NOX inhibitors have increased the evidence for pathophysiological roles of NADPH oxidases. However, in comparison to knockout mouse models, NOX inhibitors have limited isoform selectivity. Thus, their use does not enable clear statements on the involvement of individual NOX isoforms in a given disease. Future Directions: The development of isoform-selective NOX inhibitors and biologicals will enable reliable validation of specific NOX isoforms in disease models other than the mouse. Finally, GKT137831, the first NOX inhibitor in clinical development, is poised to provide proof of principle for the clinical potential of NOX inhibition. Antioxid. Redox Signal. 23, 406-427.

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“…Utilising this model has led to significant insight into a role for oxidant stress in driving diabetic neovascularisation. For example, in NOX1, 2 and 4 knockout mice, the NOX1 isoform was shown to be the predominant isoform driving retinal neovascularisation 92. Of significance, NOX1 knockout mice showed reduced adherence of inflammatory leucocytes to the vasculature coupled with a lower abundance of the macrophage‐like cells of the retina, namely the microglial cells, suggesting an interplay between reduced oxidative stress and pro‐inflammatory mediators.…”

Section: Diabetic Retinopathy Antioxidant Defences and Immunotherapiesmentioning

confidence: 99%

Recent novel approaches to limit oxidative stress and inflammation in diabetic complications

et al. 2018

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Diabetes is considered a major burden on the healthcare system of Western and non‐Western societies with the disease reaching epidemic proportions globally. Diabetic patients are highly susceptible to developing micro‐ and macrovascular complications, which contribute significantly to morbidity and mortality rates. Over the past decade, a plethora of research has demonstrated that oxidative stress and inflammation are intricately linked and significant drivers of these diabetic complications. Thus, the focus now has been towards specific mechanism‐based strategies that can target both oxidative stress and inflammatory pathways to improve the outcome of disease burden. This review will focus on the mechanisms that drive these diabetic complications and the feasibility of emerging new therapies to combat oxidative stress and inflammation in the diabetic milieu.

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NADPH Oxidase, NOX1, Mediates Vascular Injury in Ischemic Retinopathy

Abstract: Our findings suggest that strategies targeting NOX1 have the potential to be effective treatments for a range of ischemic retinopathies.

Cited by 109 publications

References 57 publications

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

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

Evolution of NADPH Oxidase Inhibitors: Selectivity and Mechanisms for Target Engagement

Recent novel approaches to limit oxidative stress and inflammation in diabetic complications

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