title: Mitochondrial oxidative stress promotes atrial fibrillation.
abstract: Oxidative stress has been suggested to play a role in the pathogenesis of atrial fibrillation (AF). Indeed, the prevalence of AF increases with age as does oxidative stress. However, the mechanisms linking redox state to AF are not well understood. In this study we identify a link between oxidative stress and aberrant intracellular Ca(2+) release via the type 2 ryanodine receptor (RyR2) that promotes AF. We show that RyR2 are oxidized in the atria of patients with chronic AF compared with individuals in sinus rhythm. To dissect the molecular mechanism linking RyR2 oxidation to AF we used two murine models harboring RyR2 mutations that cause intracellular Ca(2+) leak. Mice with intracellular Ca(2+) leak exhibited increased atrial RyR2 oxidation, mitochondrial dysfunction, reactive oxygen species (ROS) production and AF susceptibility. Both genetic inhibition of mitochondrial ROS production and pharmacological treatment of RyR2 leakage prevented AF. Collectively, our results indicate that alterations of RyR2 and mitochondrial ROS generation form a vicious cycle in the development of AF. Targeting this previously unrecognized mechanism could be useful in developing effective interventions to prevent and treat AF.
authors.affiliation: Department of Physiology and Cellular Biophysics, The Wu Center for Molecular Cardiology, and.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Xie
authors.affiliation: Department of Physiology and Cellular Biophysics, The Wu Center for Molecular Cardiology, and.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Santulli
authors.affiliation: Department of Physiology and Cellular Biophysics, The Wu Center for Molecular Cardiology, and.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Reiken
authors.affiliation: Department of Physiology and Cellular Biophysics, The Wu Center for Molecular Cardiology, and.
authors.forename: Qi
authors.initials: Q
authors.lastname: Yuan
authors.affiliation: Department of Physiology and Cellular Biophysics, The Wu Center for Molecular Cardiology, and.
authors.forename: Brent W
authors.initials: BW
authors.lastname: Osborne
authors.affiliation: Department of Physiology and Cellular Biophysics, The Wu Center for Molecular Cardiology, and.
authors.forename: Bi-Xing
authors.initials: BX
authors.lastname: Chen
authors.affiliation: 1] Department of Physiology and Cellular Biophysics, The Wu Center for Molecular Cardiology, and [2] Department of Medicine, College of Physicians and Surgeons of Columbia University Medical Center, New York, NY, USA.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Marks
mesh_terms: D000367:Age Factors; D000818:Animals; D001281:Atrial Fibrillation / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D006325:Heart Atria / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism; D013841:Thiazepines / Q000494:pharmacology
chemical_list: D017382:Reactive Oxygen Species; D019837:Ryanodine Receptor Calcium Release Channel; C540746:S-107 compound; D013841:Thiazepines; D002118:Calcium