Nitrite Confers Preconditioning and Cytoprotection After Ischemia/Reperfusion Injury Through the Modulation of Mitochondrial Function.

SIGNIFICANCE: Nitrite is now recognized as an intrinsic signaling molecule that mediates a number of biological processes. One of the most reproducible effects of nitrite is its ability to mediate cytoprotection after ischemia/reperfusion (I/R). This robust phenomenon has been reproduced by a number of investigators in varying animal models focusing on different target organs. Furthermore, nitrite's cytoprotective versatility is highlighted by its ability to mediate delayed preconditioning and remote conditioning in addition to acute protection. RECENT ADVANCES: In the last 10 years, significant progress has been made in elucidating the mechanisms underlying nitrite-mediated ischemic tolerance. CRITICAL ISSUES: The mitochondrion, which is essential to both the progression of I/R injury and the protection afforded by preconditioning, has emerged as a major subcellular target for nitrite. This review will outline the role of the mitochondrion in I/R injury and preconditioning, review the accumulated preclinical studies demonstrating nitrite-mediated cytoprotection, and finally focus on the known interactions of nitrite with mitochondria and their role in the mechanism of nitrite-mediated ischemic tolerance. FUTURE DIRECTIONS: These studies set the stage for current clinical trials testing the efficacy of nitrite to prevent warm and cold I/R injury.