The NOX toolbox: validating the role of NADPH oxidases in physiology and disease

Abstract

Reactive oxygen species (ROS) are cellular signals but also disease triggers; their relative excess (oxidative stress) or shortage (reductive stress) compared to reducing equivalents are potentially deleterious. This may explain why antioxidants fail to combat diseases that correlate with oxidative stress. Instead, targeting of disease-relevant enzymatic ROS sources that leaves physiological ROS signaling unaffected may be more beneficial. NADPH oxidases are the only known enzyme family with the sole function to produce ROS. Of the catalytic NADPH oxidase subunits (NOX), NOX4 is the most widely distributed isoform. We provide here a critical review of the currently available experimental tools to assess the role of NOX and especially NOX4, i.e. knock-out mice, siRNAs, antibodies, and pharmacological inhibitors. We then focus on the characterization of the small molecule NADPH oxidase inhibitor, VAS2870, in vitro and in vivo, its specificity, selectivity, and possible mechanism of action. Finally, we discuss the validation of NOX4 as a potential therapeutic target for indications including stroke, heart failure, and fibrosis.

Contribution of NADPH-oxidase to the establishment of hippocampal neuronal polarity in culture

“…Those chosen were gp91 ds-tat (5 µM), a peptide that inhibits p47 phox association with gp91 phox (Rey et al, 2001), VAS2870 (5 µM), a molecule that blocks the assembly of the NOX complex (Altenhofer et al, 2012) and apocynin (100 µM), which blocks p47 phox translocation to the plasma membrane (Ximenes et al, 2007). Neurons were fixed at 18 h of culture to evaluate the development of neuronal polarity ( Fig.…”

Genetic Targeting or Pharmacologic Inhibition of NADPH Oxidase Nox4 Provides Renoprotection in Long-Term Diabetic Nephropathy

“…[4][5][6]19 With respect to pharmacologic intervention, previous studies relied on nonspecific inhibitors of ROS formation, such as apocynin, a drug that has also been reported to interfere with Rho kinase. 30,31 Therefore, we postulate that this longer-term study is potentially more relevant with respect to clinical target validation.…”

Hemorheological abnormalities in human arterial hypertension

“…But some doubts have been raised against this statement (Forconi and Gori, 2009;Salazar Vásquez et al, 2011). Hyperviscosity might share the destiny of free radicals, traditionally considered dangerous byproducts of metabolism and more recently seen as mediators in some physiological processes (Altenhöfer et al, 2012). In a similar way, hyperviscosity may act as a homeostatic factor in particular pathophysiological contexts.…”