Project I A significant discovery made during the current cycle of this PPG was that effectiveness of anesthetic cardioprotection becomes attenuated in diabetic animals or in hyperglycemic conditions. We have now developed a clinically relevant model of anesthetic cardioprotection using human cardiomyocytes derived from induced pluripotent stem cells, obtained from both non-diabetic and type 2 diabetic patients. This in vitro model of human disease will enable developmental and comparative studies of normal and diabetic cardiomyocytes to address cellular and environmental mechanisms responsible for attenuation of cardioprotection efficacy in diabetics. The working hypothesis is that diabetes-related conditions increase vulnerability to stress through acute and progressive actions on mitochondria and that our strategies can reverse this diabetic phenotype. On the basis of our progress and exciting preliminary data: 1. We will determine anesthetic-induced alterations of mitochondrial bioenergetics and Ca2+ homeostasis in human ventricular cardiomyocytes (Aim 1); 2. Investigate the role of mitochondrial fission and reactive oxygen species during glucolipotoxicity (Aim 2) and; 3. Restore anesthetic cardioprotection during glucolipotoxicity in vitro and in the animal model of diabetes using pharmacological strategies (Aim 3). In summary, the cellular and molecular mechanisms that abolish volatile anesthetic cardioprotection in the diabetic heart are unknown and there are no known treatments to reverse this effect. We will focus our efforts on examination of the signaling and mitochondrial mechanisms in non-diabetic and type 2 diabetic patient-derived cardiomyocytes. Our studies will provide novel mechanistic information on the role of mitochondria and important signaling pathways that modulate cardioprotection in diabetes, and expand on the reversal of diabetic phenotype by attenuation of mitochondrial fission and reversal of nitric oxide synthase uncoupling that will be tested in a diabetic animal model.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZGM1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Medical College of Wisconsin
United States
Zip Code
Bosnjak, Zeljko J; Ge, Zhi-Dong (2017) The application of remote ischemic conditioning in cardiac surgery. F1000Res 6:928
Liu, Yanan; Baumgardt, Shelley L; Fang, Juan et al. (2017) Transgenic overexpression of GTP cyclohydrolase 1 in cardiomyocytes ameliorates post-infarction cardiac remodeling. Sci Rep 7:3093
Sedlic, Filip; Muravyeva, Maria Y; Sepac, Ana et al. (2017) Targeted Modification of Mitochondrial ROS Production Converts High Glucose-Induced Cytotoxicity to Cytoprotection: Effects on Anesthetic Preconditioning. J Cell Physiol 232:216-24
Mattson, David L; Liang, Mingyu (2017) Hypertension: From GWAS to functional genomics-based precision medicine. Nat Rev Nephrol 13:195-196
Stowe, David F; Yang, Meiying; Heisner, James S et al. (2017) Endogenous and Agonist-induced Opening of Mitochondrial Big Versus Small Ca2+-sensitive K+ Channels on Cardiac Cell and Mitochondrial Protection. J Cardiovasc Pharmacol 70:314-328
Chuppa, Sandra; Liang, Mingyu; Liu, Pengyuan et al. (2017) MicroRNA-21 regulates peroxisome proliferator-activated receptor alpha, a molecular mechanism of cardiac pathology in Cardiorenal Syndrome Type 4. Kidney Int :
Camara, Amadou K S; Zhou, YiFan; Wen, Po-Chao et al. (2017) Mitochondrial VDAC1: A Key Gatekeeper as Potential Therapeutic Target. Front Physiol 8:460
Baker, Maria Angeles; Davis, Seth J; Liu, Pengyuan et al. (2017) Tissue-Specific MicroRNA Expression Patterns in Four Types of Kidney Disease. J Am Soc Nephrol 28:2985-2992
Liu, Yanan; Yan, Yasheng; Inagaki, Yasuyoshi et al. (2017) Insufficient Astrocyte-Derived Brain-Derived Neurotrophic Factor Contributes to Propofol-Induced Neuron Death Through Akt/Glycogen Synthase Kinase 3?/Mitochondrial Fission Pathway. Anesth Analg 125:241-254
Yang, MeiYing; Camara, Amadou K S; Aldakkak, Mohammed et al. (2017) Identity and function of a cardiac mitochondrial small conductance Ca2+-activated K+ channel splice variant. Biochim Biophys Acta 1858:442-458

Showing the most recent 10 out of 124 publications