title: Modeling Local X-ROS and Calcium Signaling in the Heart.
abstract: Stretching single ventricular cardiac myocytes has been shown experimentally to activate transmembrane nicotinamide adenine dinucleotide phosphate oxidase type 2 to produce reactive oxygen species (ROS) and increase the Ca2+ spark rate in a process called X-ROS signaling. The increase in Ca2+ spark rate is thought to be due to an increase in ryanodine receptor type 2 (RyR2) open probability by direct oxidation of the RyR2 protein complex. In this article, a computational model is used to examine the regulation of ROS and calcium homeostasis by local, subcellular X-ROS signaling and its role in cardiac excitation-contraction coupling. To this end, a four-state RyR2 model was developed that includes an X-ROS-dependent RyR2 mode switch. When activated, [Ca2+]i-sensitive RyR2 open probability increases, and the Ca2+ spark rate changes in a manner consistent with experimental observations. This, to our knowledge, new model is used to study the transient effects of diastolic stretching and subsequent ROS production on RyR2 open probability, Ca2+ sparks, and the myoplasmic calcium concentration ([Ca2+]i) during excitation-contraction coupling. The model yields several predictions: 1) [ROS] is produced locally near the RyR2 complex during X-ROS signaling and increases by an order of magnitude more than the global ROS signal during myocyte stretching; 2) X-ROS activation just before the action potential, corresponding to ventricular filling during diastole, increases the magnitude of the Ca2+ transient; 3) during prolonged stretching, the X-ROS-induced increase in Ca2+ spark rate is transient, so that long-sustained stretching does not significantly increase sarcoplasmic reticulum Ca2+ leak; and 4) when the chemical reducing capacity of the cell is decreased, activation of X-ROS signaling increases sarcoplasmic reticulum Ca2+ leak and contributes to global oxidative stress, thereby increases the possibility of arrhythmia. The model provides quantitative information not currently obtainable through experimental means and thus provides a framework for future X-ROS signaling experiments.
authors.affiliation: Department of Molecular Neuroscience, School of Systems Biology and The Krasnow Institute for Advanced Study, George Mason University, Fairfax, Virginia.
authors.forename: Sarita
authors.initials: S
authors.lastname: Limbu
authors.affiliation: Department of Molecular Neuroscience, School of Systems Biology and The Krasnow Institute for Advanced Study, George Mason University, Fairfax, Virginia.
authors.forename: Tuan M
authors.initials: TM
authors.lastname: Hoang-Trong
authors.affiliation: Department of Physiology, Pennsylvania Muscle Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Prosser
authors.affiliation: Center for Biomedical Engineering and Technology and Department of Physiology University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: W Jonathan
authors.initials: WJ
authors.lastname: Lederer
authors.affiliation: Department of Molecular Neuroscience, School of Systems Biology and The Krasnow Institute for Advanced Study, George Mason University, Fairfax, Virginia; Center for Biomedical Engineering and Technology and Department of Physiology University of Maryland School of Medicine, Baltimore, Maryland. Electronic address: sjafri@gmu.edu.
authors.forename: M Saleet
authors.initials: MS
authors.lastname: Jafri
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016276:Ventricular Function
chemical_list: D017382:Reactive Oxygen Species