Liver dysfunction or failure, as a result of hepatic ischemia/reperfusion (I/R), is a leading cause of morbidity and mortality for patients who have undergone liver transplantation surgery. Currently, no therapeutic strategy exists and the ever growing gap between supply and demand for donors has forced the consideration of cadaveric or steatotic graphs, which are very susceptible to I/R. Because intervention on more than one level is likely needed to allow for the recovery of cellular and organ failure, the most promising protective strategy against I/R injury explored in the last few years is preconditioning. Therefore, ischemic preconditioning or pharmacological interventions that mimic these effects may have the greatest potential to improve clinical outcome in liver transplantation and liver surgery. Recently, nitrite through the generation of nitric oxide (NO) has been shown to have cytoprotective effects in the setting of hepatic I/R, suggesting that nitrite may serve as a biological storage reserve of NO subsurving a critical function in tissue protection from ischemic injury. Furthermore, preliminary data from our lab indicates that the administration of nitrite 24 hours prior to I/R protects the liver against injury. Moreover, nitrite preconditioning was found to attenuate the l/R-induced suppression of mitochondrial respiration. Therefore, the objective of this proposal is to delve into the role of the mitochondria in nitrite mediated hepatic preconditioning with the central hypothesis being that nitrite preconditioning preserves the structure and function of the mitochondria following hepatic I/R, thereby attenuating hepatocellular injury. The rationale for the proposed research is that identifying the mechanisms of nitrite preconditioning may provide a basis for extending the clinical application to patients facing liver transplantation or liver surgery. So, we plan to test our central hypothesis and accomplish the objective of the proposed study by pursuing two specific aims.
Specific aim 1 will further expand on our preliminary data by exploring the-protection of the mitochondria through the evaluation of mitochondrial matrix volume, mitochondrial membrane potential, mitochondiral uptake of calcium, mitochondrial respiration of the different complexes, ATP production, redox potential, ROS production, and finally the release of cytochrome C from the mitochondria into the cytosol.
Specific aim 2 will take a step back and explore the signaling mechanisms of nitrite preconditioning by examining the role of mitochondrial K+ channels. We believe that nitrite, through its conversion to NO, protects the mitochondria from a subsequent I/R injury by mediating the opening of the mitochondrial K+ channels, mKATP and mKCa, via the molecular signaling of PKC and PKA, respectively. ? ? ?
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