Combating oxidative stress in vascular disease: NADPH oxidases as therapeutic targets

Abstract

NADPH oxidases are a family of enzymes that generate reactive oxygen species (ROS). The ROS generated by NADPH oxidases have crucial roles in various physiological processes, including innate immunity and modulation of redox-dependent signalling cascades. Excessive ROS production by an overactive NADPH oxidase system in cells of the artery wall may set in motion a vicious cycle of radical and non-radical oxidant generation in various cellular compartments, which disrupts redox circuits. This can lead to the initiation and progression of vascular disease that may ultimately lead to heart attacks and strokes. Blocking excessive ROS production by blocking NADPH oxidases is likely to be a far superior approach for preventing the progression of vascular disease than using antioxidant drugs, which scavenge ROS. This Review first provides an overview of the mechanisms by which ROS can cause vascular disease and the possible reasons why previous attempts to eliminate these species with antioxidants failed. We summarize the evidence that NADPH oxidases are key generators of ROS — in the blood vessel wall and other tissues — during cardiovascular diseases, with a particular focus on the NADPH oxidase 1 (NOX1) and NOX2 oxidase isoforms. We also describe some common and emerging putative NADPH oxidase inhibitors. In addition, we highlight the crucial role of the NADPH oxidase regulatory subunit, p47phox, in the activity of vascular NOX1 and NOX2 oxidases, and suggest how a better understanding of its specific molecular interactions may enable the development of novel isoform-selective drugs to prevent or treat cardiovascular diseases.