Redox regulation of protein kinases as a modulator of vascular function

Reactive oxygen species (ROS) are continuously generated in vascular tissues by various oxidoreductase enzymes. They contribute to normal cell signaling, and modulate vascular smooth muscle tone and endothelial permeability in response to physiological agonists and to various cellular stresses and environmental factors, such as hypoxia. While concentrations of ROS are normally tightly controlled by cellular redox buffer systems, if produced in excess they may contribute to vascular disease. Protein kinases are essential components of most cell signaling pathways, including those involving ROS. The functioning of several members of this highly diverse group of enzymes, which include receptor and nonreceptor tyrosine kinases, protein kinase C, mitogen-activated kinases, and Rho-kinase, are modified by ROS, either through direct oxidative modification or indirectly through modification of associated proteins such as tyrosine phosphatases and monomeric G proteins. In this review, we discuss the molecular mechanisms of redox modification of these proteins, the downstream pathways affected, the often complex interaction between major kinase pathways, and feedback to ROS production itself. We also discuss complicating factors such as differential actions of superoxide anion and hydrogen peroxide, questions concerning concentration dependence, and the significance of signaling microdomains.