The overall objective of this Project is to directly investigate the specific effects of volatile anesthetics on mitochondrial function that lead to anesthetic-induced preconditioning (ARC). We specifically hypothesize that anesthetics induce changes in mitochondrial bioenergetics and ion fluxes which through downstream mechanisms inhibit or delay opening of the mitochondrial permeability transition (PT) pore, a central event during ischemia and reperfusion injury. During the current cycle we identified a role for the sarcolemmal KATP channels as protectors against oxidative stress and apoptosis. We also obtained evidence on the novel local regulation of the mitochondrial KATP channel by PKC, ROS and NO'. We showed that mitochondria isolated from hearts subjected to APC were more resistant to Ca2+-induced PT pore opening in a PCK dependent manner. Together these data strongly suggest that regulation of mitochondria function is central for cardioprotection following transient anesthetic exposure. Based on these very exciting results and the development of novel state-of-the-art experimental approaches, Project II will furnish strong evidence that inhibition of PT pore opening is an ultimate mechanism by which APC actually affects cardioprotection. We will address the following Specific Aims and hypotheses:
Aim 1. Determine the direct effects of volatile anesthetics on mitochondrial bioenergetics, ion homeostasis and proteome.
Aim 2. Characterize how anesthetics modulate PT pore opening.
Aim 3. Determine the contribution of sarcKATp channel to anesthetic-induced mitochondrial protection.
Aim 4. Apply computational models to quantify and predict the effects of anesthetics on mitochondrial bioenergetics and function. In summary, the mitochondrion is not only a downstream target, but also an upstream initiator of APC. These studies will provide novel and mechanistic information of APC signaling pathways at the mitochondrial level which should lead to novel therapeutic approaches to treat ischemia reperfusion injury. Lay description: We will examine how general anesthetics protect the heart against ischemia/reperfusion injury by interactions between mitochondria and their cytosolic envelope. These results will furnish valuable information for translating protective therapies to clinical practice.
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|Pannala, Venkat R; Camara, Amadou K S; Dash, Ranjan K (2016) Modeling the detailed kinetics of mitochondrial cytochrome c oxidase: Catalytic mechanism and nitric oxide inhibition. J Appl Physiol (1985) 121:1196-1207|
|Ranji, Mahsa; Motlagh, Mohammad Masoudi; Salehpour, Fahimeh et al. (2016) Optical Cryoimaging Reveals a Heterogeneous Distribution of Mitochondrial Redox State in ex vivo Guinea Pig Hearts and Its Alteration During Ischemia and Reperfusion. IEEE J Transl Eng Health Med 4:1800210|
|Blomeyer, Christoph A; Bazil, Jason N; Stowe, David F et al. (2016) Mg(2+) differentially regulates two modes of mitochondrial Ca(2+) uptake in isolated cardiac mitochondria: implications for mitochondrial Ca(2+) sequestration. J Bioenerg Biomembr 48:175-88|
|Wu, Hsiang-En; Baumgardt, Shelley L; Fang, Juan et al. (2016) Cardiomyocyte GTP Cyclohydrolase 1 Protects the Heart Against Diabetic Cardiomyopathy. Sci Rep 6:27925|
|Bosnjak, Zeljko J; Logan, Sarah; Liu, Yanan et al. (2016) Recent Insights Into Molecular Mechanisms of Propofol-Induced Developmental Neurotoxicity: Implications for the Protective Strategies. Anesth Analg 123:1286-1296|
|Afzal, Muhammad Z; Reiter, Melanie; Gastonguay, Courtney et al. (2016) Nicorandil, a Nitric Oxide Donor and ATP-Sensitive Potassium Channel Opener, Protects Against Dystrophin-Deficient Cardiomyopathy. J Cardiovasc Pharmacol Ther 21:549-562|
|Baumgardt, Shelley L; Paterson, Mark; Leucker, Thorsten M et al. (2016) Chronic Co-Administration of Sepiapterin and L-Citrulline Ameliorates Diabetic Cardiomyopathy and Myocardial Ischemia/Reperfusion Injury in Obese Type 2 Diabetic Mice. Circ Heart Fail 9:e002424|
|Dash, Ranjan K; Korman, Ben; Bassingthwaighte, James B (2016) Simple accurate mathematical models of blood HbO2 and HbCO2 dissociation curves at varied physiological conditions: evaluation and comparison with other models. Eur J Appl Physiol 116:97-113|
|Twaroski, Danielle; Bosnjak, Zeljko J; Bai, Xiaowen (2015) MicroRNAs: New Players in Anesthetic-Induced Developmental Neurotoxicity. Pharm Anal Acta 6:357|
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