title: Down-regulation of the small conductance calcium-activated potassium channels in diabetic mouse atria.
abstract: The small conductance Ca(2+)-activated K(+) (SK) channels have recently been found to be expressed in the heart, and genome-wide association studies have shown that they are implicated in atrial fibrillation. Diabetes mellitus is an independent risk factor of atrial fibrillation, but the ionic mechanism underlying this relationship remains unclear. We hypothesized that SK channel function is abnormal in diabetes mellitus, leading to altered cardiac electrophysiology. We found that in streptozotocin-induced diabetic mice, the expression of SK2 and SK3 isoforms was down-regulated by 85 and 92%, respectively, whereas that of SK1 was not changed. SK currents from isolated diabetic mouse atrial myocytes were significantly reduced compared with controls. The resting potentials of isolated atrial preparations were similar between control and diabetic mice, but action potential durations were significantly prolonged in the diabetic atria. Exposure to apamin significantly prolonged action potential durations in control but not in diabetic atria. Production of reactive oxygen species was significantly increased in diabetic atria and in high glucose-cultured HL-1 cells, whereas exposure of HL-1 cells in normal glucose culture to H2O2 reduced the expression of SK2 and SK3. Tyrosine nitration in SK2 and SK3 was significantly increased by high glucose culture, leading to accelerated channel turnover. Treatment with Tiron prevented these changes. Our results suggest that increased oxidative stress in diabetes results in SK channel-associated electrical remodeling in diabetic atria and may promote arrhythmogenesis.
authors.affiliation: From the Department of Internal Medicine, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota 55905, Department of Cardiovascular Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Fu
authors.initials: F
authors.lastname: Yi
authors.affiliation: From the Department of Internal Medicine, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota 55905, Department of Cardiology, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200025, China.
authors.forename: Tian-You
authors.initials: TY
authors.lastname: Ling
authors.affiliation: From the Department of Internal Medicine, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Tong
authors.initials: T
authors.lastname: Lu
authors.affiliation: From the Department of Internal Medicine, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Xiao-Li
authors.initials: XL
authors.lastname: Wang
authors.affiliation: From the Department of Internal Medicine, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota 55905, Department of Emergency Medicine, Henan Provincial People's Hospital, Affiliated Hospital of Zhengzhou University, Zhengzhou 450003, Henan, China.
authors.forename: Jingchao
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, and.
authors.forename: William C
authors.initials: WC
authors.lastname: Claycomb
authors.affiliation: Department of Internal Medicine, Division of Cardiovascular Diseases, Mayo Clinic, Phoenix, Arizona 85255.
authors.forename: Win-Kuang
authors.initials: WK
authors.lastname: Shen
authors.affiliation: From the Department of Internal Medicine, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota 55905, Lee.honchi@mayo.edu.
authors.forename: Hon-Chi
authors.initials: HC
authors.lastname: Lee
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D002460:Cell Line; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000235:genetics / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D006325:Heart Atria / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D051379:Mice; D018384:Oxidative Stress; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: C496898:Kcnn2 protein, mouse; C496900:Kcnn3 protein, mouse; D051640:Small-Conductance Calcium-Activated Potassium Channels
keywords: Cardiomyocyte; Diabetes; HL-1 Cells; Mouse; Oxidative Stress; Patch Clamp; Potassium Channel; SK Channels