The overall objective of this Project is to directly investigate the specific effects of volatile anestheticson mitochondrial function that lead to anesthetic-induced preconditioning (ARC). We specifically hypothesizethat anesthetics induce changes in mitochondrial bioenergetics and ion fluxes which through downstreammechanisms inhibit or delay opening of the mitochondrial permeability transition (PT) pore, a central eventduring ischemia and reperfusion injury. During the current cycle we identified a role for the sarcolemmal KATPchannels as protectors against oxidative stress and apoptosis. We also obtained evidence on the novel localregulation of the mitochondrial KATP channel by PKC, ROS and NO'. We showed that mitochondria isolatedfrom hearts subjected to APC were more resistant to Ca2+-induced PT pore opening in a PCK dependentmanner. Together these data strongly suggest that regulation of mitochondria function is central forcardioprotection following transient anesthetic exposure.Based on these very exciting results and the development of novel state-of-the-art experimentalapproaches, Project II will furnish strong evidence that inhibition of PT pore opening is an ultimatemechanism by which APC actually affects cardioprotection. We will address the following Specific Aims andhypotheses:
Aim 1. Determine the direct effects of volatile anesthetics on mitochondrial bioenergetics, ionhomeostasis and proteome.
Aim 2. Characterize how anesthetics modulate PT pore opening.
Aim 3. Determine the contribution of sarcKATp channel to anesthetic-induced mitochondrialprotection.
Aim 4. Apply computational models to quantify and predict the effects of anesthetics on mitochondrialbioenergetics and function.In summary, the mitochondrion is not only a downstream target, but also an upstream initiator ofAPC. These studies will provide novel and mechanistic information of APC signaling pathways at themitochondrial level which should lead to novel therapeutic approaches to treat ischemia reperfusion injury.Lay description: We will examine how general anesthetics protect the heart againstischemia/reperfusion injury by interactions between mitochondria and their cytosolic envelope. These resultswill furnish valuable information for translating protective therapies to clinical practice.
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