title: SK channel enhancers attenuate Ca2+-dependent arrhythmia in hypertrophic hearts by regulating mito-ROS-dependent oxidation and activity of RyR.
abstract: Plasmamembrane small conductance Ca2+-activated K+ (SK) channels were implicated in ventricular arrhythmias in infarcted and failing hearts. Recently, SK channels were detected in the inner mitochondria membrane (IMM) (mSK), and their activation protected from acute ischaemia-reperfusion injury by reducing intracellular levels of reactive oxygen species (ROS). We hypothesized that mSK play an important role in regulating mitochondrial function in chronic cardiac diseases. We investigated the role of mSK channels in Ca2+-dependent ventricular arrhythmia using rat model of cardiac hypertrophy induced by banding of the ascending aorta thoracic aortic banding (TAB).
  
  
  
  Dual Ca2+ and membrane potential optical mapping of whole hearts derived from TAB rats revealed that membrane-permeable SK enhancer NS309 (2 μM) improved aberrant Ca2+ homeostasis and abolished VT/VF induced by β-adrenergic stimulation. Using whole cell patch-clamp and confocal Ca2+ imaging of cardiomyocytes derived from TAB hearts (TCMs) we found that membrane-permeable SK enhancers NS309 and CyPPA (10 μM) attenuated frequency of spontaneous Ca2+ waves and delayed afterdepolarizations. Furthermore, mSK inhibition enhanced (UCL-1684, 1 μM); while activation reduced mitochondrial ROS production in TCMs measured with MitoSOX. Protein oxidation assays demonstrated that increased oxidation of ryanodine receptors (RyRs) in TCMs was reversed by SK enhancers. Experiments in permeabilized TCMs showed that SK enhancers restored SR Ca2+ content, suggestive of substantial improvement in RyR function.
  
  
  
  These data suggest that enhancement of mSK channels in hypertrophic rat hearts protects from Ca2+-dependent arrhythmia and suggest that the protection is mediated via decreased mitochondrial ROS and subsequent decreased oxidation of reactive cysteines in RyR, which ultimately leads to stabilization of RyR-mediated Ca2+ release.
authors.affiliation: Department of Medicine, Division of Cardiology, Cardiovascular Research Center, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, 1 Hoppin Street, Providence, RI, 02903-4141, USA.
authors.forename: Tae Yun
authors.initials: TY
authors.lastname: Kim
authors.affiliation: Department of Medicine, Division of Cardiology, Cardiovascular Research Center, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, 1 Hoppin Street, Providence, RI, 02903-4141, USA.
authors.forename: Radmila
authors.initials: R
authors.lastname: Terentyeva
authors.affiliation: Department of Medicine, Division of Cardiology, Cardiovascular Research Center, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, 1 Hoppin Street, Providence, RI, 02903-4141, USA.
authors.forename: Karim H F
authors.initials: KH
authors.lastname: Roder
authors.affiliation: Department of Medicine, Division of Cardiology, Cardiovascular Research Center, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, 1 Hoppin Street, Providence, RI, 02903-4141, USA.
authors.forename: Weiyan
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Medicine, Division of Cardiology, Cardiovascular Research Center, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, 1 Hoppin Street, Providence, RI, 02903-4141, USA.
authors.forename: Man
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Medicine, Division of Cardiology, Cardiovascular Research Center, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, 1 Hoppin Street, Providence, RI, 02903-4141, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Greener
authors.affiliation: Division of Cancer and Genetics, School of Medicine, Wales Heart Research Institute, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK.
authors.forename: Shanna
authors.initials: S
authors.lastname: Hamilton
authors.affiliation: Department of Medicine, Division of Cardiology, Cardiovascular Research Center, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, 1 Hoppin Street, Providence, RI, 02903-4141, USA.
authors.forename: Iuliia
authors.initials: I
authors.lastname: Polina
authors.affiliation: Department of Medicine, Division of Cardiology, Cardiovascular Research Center, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, 1 Hoppin Street, Providence, RI, 02903-4141, USA.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Murphy
authors.affiliation: Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, The Warren, Alpert Medical School of Brown University, 1 Hoppin Street, Providence, RI 02903-4141, USA.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Clements
authors.affiliation: Department of Medicine, Division of Cardiology, Cardiovascular Research Center, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, 1 Hoppin Street, Providence, RI, 02903-4141, USA.
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Dudley
authors.affiliation: Department of Medicine, Division of Cardiology, Cardiovascular Research Center, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, 1 Hoppin Street, Providence, RI, 02903-4141, USA.
authors.forename: Gideon
authors.initials: G
authors.lastname: Koren
authors.affiliation: Department of Medicine, Division of Cardiology, Cardiovascular Research Center, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, 1 Hoppin Street, Providence, RI, 02903-4141, USA.
authors.forename: Bum-Rak
authors.initials: BR
authors.lastname: Choi
authors.affiliation: Department of Medicine, Division of Cardiology, Cardiovascular Research Center, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, 1 Hoppin Street, Providence, RI, 02903-4141, USA.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Terentyev
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D020013:Calcium Signaling / Q000187:drug effects*; D006332:Cardiomegaly / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D007211:Indoles / Q000494:pharmacology*; D007700:Kinetics; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction; D010091:Oximes / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects* / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000819:agonists* / Q000378:metabolism
chemical_list: C493327:6,7-dichloro-1H-indole-2,3-dione 3-oxime; D007211:Indoles; C496896:Kcnn1 protein, rat; C496899:Kcnn2 protein, rat; C496901:Kcnn3 protein, rat; D010091:Oximes; D011720:Pyrazoles; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D019837:Ryanodine Receptor Calcium Release Channel; D051640:Small-Conductance Calcium-Activated Potassium Channels; C552889:cyclohexyl-(2-(3,5-dimethylpyrazol-1-yl)-6-methylpyrimidin-4-yl)amine
keywords: Cardiac hypertrophy; Reactive oxygen species; Ryanodine receptor; Small conductance Ca2+-activated K+ channels; Ventricular arrhythmia