title: Targeted Modification of Mitochondrial ROS Production Converts High Glucose-Induced Cytotoxicity to Cytoprotection: Effects on Anesthetic Preconditioning.
abstract: Contradictory reports on the effects of diabetes and hyperglycemia on myocardial infarction range from cytotoxicity to cytoprotection. The study was designed to investigate acute effects of high glucose-driven changes in mitochondrial metabolism and osmolarity on adaptive mechanisms and resistance to oxidative stress of isolated rat cardiomyocytes. We examined the effects of high glucose on several parameters of mitochondrial bioenergetics, including changes in oxygen consumption, mitochondrial membrane potential, and NAD(P)H fluorometry. Effects of high glucose on the endogenous cytoprotective mechanisms elicited by anesthetic preconditioning (APC) and the mediators of cell injury were also tested. These experiments included real-time measurements of reactive oxygen species (ROS) production and mitochondrial permeability transition pore (mPTP) opening in single cells by laser scanning fluorescence confocal microscopy, and cell survival assay. High glucose rapidly enhanced mitochondrial energy metabolism, observed by increase in NAD(P)H fluorescence intensity, oxygen consumption, and mitochondrial membrane potential. This substantially elevated production of ROS, accelerated opening of the mPTP, and decreased survival of cells exposed to oxidative stress. Abrogation of high glucose-induced mitochondrial hyperpolarization with 2,4 dinitrophenol (DNP) significantly, but not completely, attenuated ROS production to a level similar to hyperosmotic mannitol control. DNP treatment reversed high glucose-induced cytotoxicity to cytoprotection. Hyperosmotic mannitol treatment also induced cytoprotection. High glucose abrogated APC-induced mitochondrial depolarization, delay in mPTP opening and cytoprotection. In conclusion, high glucose-induced mitochondrial hyperpolarization abolishes APC and augments cell injury. Attenuation of high glucose-induced ROS production by eliminating mitochondrial hyperpolarization protects cardiomyocytes. J. Cell. Physiol. 232: 216-224, 2017. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Pathophysiology, University of Zagreb, School of Medicine, Croatia. filip.sedlic@mef.hr.
authors.forename: Filip
authors.initials: F
authors.lastname: Sedlic
authors.affiliation: Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Maria Y
authors.initials: MY
authors.lastname: Muravyeva
authors.affiliation: Department of Pathology, University of Zagreb, School of Medicine, Croatia.
authors.forename: Ana
authors.initials: A
authors.lastname: Sepac
authors.affiliation: Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Marija
authors.initials: M
authors.lastname: Sedlic
authors.affiliation: Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Anna Marie
authors.initials: AM
authors.lastname: Williams
authors.affiliation: Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Meiying
authors.initials: M
authors.lastname: Yang
authors.affiliation: Departments of Anesthesiology and Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Bai
authors.affiliation: Departments of Anesthesiology and Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Zeljko J
authors.initials: ZJ
authors.lastname: Bosnjak
mesh_terms: D000777:Anesthetics; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D008929:Mitochondria, Heart / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D000777:Anesthetics; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017382:Reactive Oxygen Species; D005947:Glucose