Volatile anesthetics (VA) induce cardioprotection, which improves mitochondrial and cellular function during ischemia/reperfusion (I/R) and reduces necrotic and apoptotic cell death. However, the functional consequenc- es of VA leading to cardioprotection against I/R injury are not well understood. Specifically, the targeted effects of VA on proteins (channels/transporters/enzymes) regulating mitochondrial and cellular function that lead to cardioprotection and the molecular mechanisms underlying this protection are not well known. In addition, it is not known how these effects/mechanisms are modified in diabetes or diabetes-related altered cellular condi- tions (e.g. glucolipotoxicity, reduced miR-21 expression), in which the protection offered by VA is less efficient or fails. We and others have shown that isoflurane (ISO) modulates sarcolemmal ion channels, including the L- type Ca2+ channel and sarcKATP channel, as well as mitochondrial complexes I and III, Na+/Ca2+ exchanger, and mitoKATP channel, in inducing cardioprotection. However, it is not known how ISO modulations of these proteins (and likely other proteins) collectively lead to the observed alterations in cellular action potentials and Ca2+ transients as well as mitochondrial bioenergetics, Ca2+ dynamics, and ROS emission under different cellu- lar conditions that lead to (impaired)cardioprotection. In Project III, we propose a systems biology approach to iteratively conduct experiments and use the measured data to computationally model and mechanistically char- acterize the specific effects and molecular mechanisms of actions of ISO on proteins regulating mitochondrial and cellular function that lead to (impaired)cardioprotection against I/R injury under different cellular conditions using isolated mitochondria and isolated myocytes from rat (Wistar: control, T2DNmtFHH: diabetic) hearts (Aims 1-2). Specifically, we will characterize how ISO modulates proteins affecting mitochondrial bioenergetics, Ca2+ dynamics, and ROS emission that regulate mPTP opening, an end effector of cardiac cell death during I/R inju- ry. The resulting cellular-level computational model will then be used as a basis for analyzing analogously measured data from iPSC-derived cardiomyocytes (CM) from non-diabetic and type 2 diabetic patients (N-CM, T2-CM) under normal, glucolipotoxic, and altered miR-21 expression conditions to determine how ISO exerts differential effects/mechanisms on the targeted proteins leading to (impaired)cardioprotection under different cellular conditions (Aim 3). Therefore, the three specific aims of this project will address several key questions that are critical for defining the targeted effects of ISO on mitochondrial and cellular function in rats (Wistar, T2DNmtFHH) as well as in iPSC-CM (N-CM, T2-CM) to mechanistically characterize how the effects are different in different cell types and how the effects are altered under altered cellular conditions (e.g. glucolipotoxicity, reduced miR-21 expression). Our overarching hypothesis is that ISO modulates mitochondrial and cellular function by its combined action on several key proteins involved in cardioprotection, and that altered cellular conditions impair these effects, and that this can be characterized by mechanistic computational modeling.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Medical College of Wisconsin
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