Vascular reactive oxygen species biology - Insights from transgenic and knockout mouse models

Abstract

Maintenance of a healthy vasculature is central to the prevention of cardiovascular disease, including atherosclerosis. Reactive oxygen and nitrogen species (ROS/RNS), such as the superoxide anion, peroxides, and peroxynitrite, are now accepted as key contributors to vascular injury, contributing to both the initiation and progression of the disease. Common risk factors such as hyperglycemia, hypertension, and hyperlipidemia are known to upregulate the major ROS producers of the vasculature such as NADPH oxidase, xanthine oxidase, and lipoxygenase to produce ROS. Mitochondria are another important source of vascular ROS, and eNOS uncoupling leads to aberrant ROS formation in the face of known cardiovascular risk factors. To counteract the increase in ROS, a number of antioxidant enzymes (e.g., superoxide dismutases, catalase, glutathione peroxidases, and peroxiredoxins) regulate ROS to maintain low steady-state levels. Vascular injury, including endothelial dysfunction, results from an imbalance between ROS/RNS production and antioxidant defenses as well as impaired repair of oxidative damage. This chapter will review evidence from knockout and transgenic murine models to evaluate (1) the contribution of the major ROS-/RNS-producing enzymes to vascular injury and (2) the protection afforded by the endogenous antioxidant defenses within the vasculature. These insights are proving invaluable in the quest for therapeutic strategies to minimize vascular oxidative stress and cellular injury.