Endothelial NADPH oxidases: which NOX to target in vascular disease?

• Endothelial cells express four NADPH oxidase isoforms: NOX1, 2, 4, and 5.
• NOX1, 2, and 5 make superoxide and cause endothelial dysfunction and vascular disease.
• NOX4 generates hydrogen peroxide and exerts protective effects on the vessel wall.
• Selective inhibitors of NOX1/2 (e.g., apocynin) hold promise as novel therapies for vascular disease.

NADPH oxidases (NOXs) are reactive oxygen species (ROS)-generating enzymes implicated in the pathophysiology of vascular diseases such as hypertension and stroke. Endothelial cells express four NOX isoforms including the superoxide-generating enzymes NOX1, NOX2, and NOX5 and the hydrogen peroxide-generating enzyme NOX4. Studies on arteries from patients with coronary artery disease, and in animals with experimentally induced hypertension, diabetes, or atherosclerosis, suggest that NOX1, NOX2, and NOX5 promote endothelial dysfunction, inflammation, and apoptosis in the vessel wall, whereas NOX4 is by contrast vasoprotective in increasing nitric oxide bioavailability and suppressing cell death pathways. Based on these findings and promising preclinical studies with the NOX1/NOX2 antagonist, apocynin, we suggest that the field is poised for clinical evaluation of NOX inhibitors as therapeutics for cardiovascular disease.