Similar to the powerful endogenous cardioprotective mechanism of ischemic preconditioning, anesthetic-induced preconditioning (APC) has emerged as an equally effective cardioprotective intervention with better risk-to-benefit ratio for the patient. During the current cycle of the Program Project we have identified key elements and mechanisms involved in APC. Central to cardioprotection is the knowledge we have gained regarding the regulation of mitochondrial function by volatile anesthetics. Given the fundamental role of mitochondria in myocardial energetics and oxidative stress, we believe that they are a promising target for protective strategies such as APC. In contrast, disease states resistant to APC (e.g. diabetes) contain fundamental disturbances of mitochondrial function. The central theme of this Program Project is to elucidate the molecular mechanisms underlying APC. Specifically, we hypothesize that attenuation of permeability transition (PT) pore opening after ischemia and reperfusion is central to many of the phenotypic differences observed after exposure to volatile anesthetics. This Program will consist of three interrelated research projects supported by two Cores. Project I (Warltier) will focus on defining the temporal sequence of activation of key cardioprotective proteins related to the regulation of NO? production via HIF1a-VEGF-NO? axis by volatile anesthetics. Disruption of these elements and their effect on sarcKATp channel activity, mitochondrial-derived ROS formation, and tissue and cell injury will be determined. Project II (Bosnjak) will elucidate mechanisms involved in volatile anesthetic-dependent modulation of PT pore opening, a critical end effector of APC. It will address several factors that are critical to the role of the PT pore in APC such as mitochondrial bioenergetics and its proteome and the contribution of sarcKATp channels. Computational models of mitochondrial bioenergetics will be used to test specific hypotheses related to the effects of volatile anesthetics. Project III (Kersten) will investigate mechanisms involved in the attenuation of APC in diabetic animals. It will exploit a novel rat model of type 2 diabetes in which we were able to selectively switch the mitochondrial genome to further dissect the role of mitochondria and eNOS-sensitive pathway during impaired APC. All three Projects will be supported by a Biochemical and Molecular Biology Core (Harder) and a Proteomics Core (Olivier). These Cores will provide state-ofthe- art techniques in gene silencing, real time PCR, mitochondrial proteome, cell cultures, mitochondrial function assays, confocal microscopy and pathology. This Program Project represents a comprehensive effort to leverage our existing infrastructure and programmatic experience in physiology, biophysics, genomics, proteomics, and computational biology to advance our understanding of the cellular and subcellular effects of anesthetics in organ protection. Our findings are likely to have a significant impact in the clinical use of volatile anesthetics.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM066730-10
Application #
8305026
Study Section
Special Emphasis Panel (ZGM1-PPBC-0 (AN))
Program Officer
Cole, Alison E
Project Start
2003-05-05
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
10
Fiscal Year
2012
Total Cost
$1,762,868
Indirect Cost
$599,259
Name
Medical College of Wisconsin
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
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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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