Multi-author review

Cellular and Molecular Life Sciences

, Volume 69, Issue 14, pp 2327-2343

Open Access This content is freely available online to anyone, anywhere at any time.

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

  • Sebastian AltenhöferAffiliated withDepartment of Pharmacology, Cardiovascular Research Institute Maastricht (CARIM), Vascular Drug Discovery Group, Faculty of Medicine, Health and Life Science, Maastricht University
  • , Pamela W. M. KleikersAffiliated withDepartment of Pharmacology, Cardiovascular Research Institute Maastricht (CARIM), Vascular Drug Discovery Group, Faculty of Medicine, Health and Life Science, Maastricht University
  • , Kim A. RadermacherAffiliated withDepartment of Pharmacology, Cardiovascular Research Institute Maastricht (CARIM), Vascular Drug Discovery Group, Faculty of Medicine, Health and Life Science, Maastricht University
  • , Peter ScheurerAffiliated withVasopharm GmbH
  • , J. J. Rob HermansAffiliated withDepartment of Pharmacology, Cardiovascular Research Institute Maastricht (CARIM), Vascular Drug Discovery Group, Faculty of Medicine, Health and Life Science, Maastricht University
  • , Paul SchiffersAffiliated withDepartment of Pharmacology, Cardiovascular Research Institute Maastricht (CARIM), Vascular Drug Discovery Group, Faculty of Medicine, Health and Life Science, Maastricht University
  • , Heidi HoAffiliated withNational Stroke Research Institute
  • , Kirstin WinglerAffiliated withDepartment of Pharmacology, Cardiovascular Research Institute Maastricht (CARIM), Vascular Drug Discovery Group, Faculty of Medicine, Health and Life Science, Maastricht University
  • , Harald H. H. W. SchmidtAffiliated withDepartment of Pharmacology, Cardiovascular Research Institute Maastricht (CARIM), Vascular Drug Discovery Group, Faculty of Medicine, Health and Life Science, Maastricht University Email author 

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.

Keywords

siRNA Antibodies NADPH oxidase inhibitor NOX4 VAS2870 NOX4 knock-out