Effects of nitrite on modulating ROS generation following ischemia and reperfusion

Abstract

It has long been known that the generation of reactive oxygen species (ROS) is a major cause of injury after ischemia/reperfusion. More recently it has emerged that the predominant source of these ROS are the mitochondria, which are specifically damaged during prolonged ischemic episodes. Several strategies have been tested to attenuate mitochondrial damage and reperfusion ROS. Most successful has been ischemic preconditioning, a procedure in which repetitive short periods of ischemia and reperfusion reduce injury from a subsequent prolonged ischemia and reperfusion. Recently, ischemic postconditioning, whereby reperfusion after prolonged ischemia is repetitively interrupted for a short period, has also been shown to equally protect as ischemic preconditioning. Both procedures activate the same down-stream kinase pathways that minimize apoptosis and tissue damage. Endothelial nitric oxide synthase is a target of these kinase pathways and nitric oxide (NO) administration can mimic its protective effect. However, the optimal NO dose is difficult to determine and excess NO levels have been shown to be detrimental. A recently described physiological storage pool of NO, nitrite, has been shown to be a potent mediator of cytoprotection after ischemia/reperfusion that mechanistically reduces mitochondrial ROS generation at reperfusion. Here, we describe the sources, bioactivaton, and mechanisms of action of nitrite and discuss the potential of this simple anion as a therapeutic to protect against ischemia/reperfusion injury.