NADPH oxidase, NOX1, mediates vascular injury in ischemic retinopathy.

Abstract

AIMS:

Ischemic retinal diseases such as retinopathy of prematurity are major causes of blindness due to damage to the retinal microvasculature. Despite this clinical situation, retinopathy of prematurity is mechanistically poorly understood. Therefore, effective preventative therapies are not available. However, hypoxic-induced increases in reactive oxygen species (ROS) have been suggested to be involved with NADPH oxidases (NOX), the only known dedicated enzymatic source of ROS. Our major aim was to determine the contribution of NOX isoforms (1, 2, and 4) to a rodent model of retinopathy of prematurity.

RESULTS:

Using a genetic approach, we determined that only mice with a deletion of NOX1, but not NOX2 or NOX4, were protected from retinal neovascularization and vaso-obliteration, adhesion of leukocytes, microglial accumulation, and the increased generation of proangiogenic and proinflammatory factors and ROS. We complemented these studies by showing that the specific NOX inhibitor, GKT137831, reduced vasculopathy and ROS levels in retina. The source of NOX isoforms was evaluated in retinal vascular cells and neuro-glial elements. Microglia, the immune cells of the retina, expressed NOX1, 2, and 4 and responded to hypoxia with increased ROS formation, which was reduced by GKT137831.

INNOVATION:

Our studies are the first to identify the NOX1 isoform as having an important role in the pathogenesis of retinopathy of prematurity.

CONCLUSIONS:

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

• Authors: Jennifer L Wilkinson-Berka, Devy Deliyanti, Indrajeetsinh Rana, Antonia G Miller, Alex Agrotis, Roksana Armani, Cédric Szyndralewiez, Kirstin Wingler, Rhian M Touyz, Mark E Cooper, Karin A Jandeleit-Dahm, Harald H H W Schmidt
• Journal: Antioxidants & redox signaling (Antioxid Redox Signal) Vol. 20 Issue 17 Pg. 2726-40 (Jun 10 2014) ISSN: 1557-7716 [Electronic] United States
• PMID: 24053718 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Membrane Glycoproteins
• Pyrazoles
• Pyrazolones
• Pyridines
• Pyridones
• Reactive Oxygen Species
• setanaxib
• CYBB protein, human
• NADPH Oxidase 1
• NADPH Oxidase 2
• NADPH Oxidase 4
• NADPH Oxidases
• NOX1 protein, human
• NOX4 protein, human

Topics

• Animals
• Disease Models, Animal
• Humans
• Ischemia (genetics, metabolism, pathology)
• Membrane Glycoproteins (biosynthesis, genetics)
• Mice
• NADPH Oxidase 1
• NADPH Oxidase 2
• NADPH Oxidase 4
• NADPH Oxidases (biosynthesis, genetics)
• Oxidation-Reduction
• Pyrazoles (administration & dosage)
• Pyrazolones
• Pyridines (administration & dosage)
• Pyridones
• Reactive Oxygen Species (metabolism)
• Retinopathy of Prematurity (genetics, metabolism, pathology)
• Vascular System Injuries (enzymology)