title: Cardiomyocyte-derived mitochondrial superoxide causes myocardial electrical remodeling by downregulating potassium channels and related molecules.
abstract: BACKGROUND
  This study was designed to investigate the role of a primary hyperoxidative stress in myocardial electrical remodeling using heterozygous heart/muscle-specific manganese superoxide dismutase-deficient (H/M-Sod2(+/-)) mice treated with L-buthionine-sulfoximine (BSO).
  
  
  RESULTS
  Both H/M-Sod2(+/-)and wild-type (WT) mice were treated with intra-peritoneal BSO or saline for 7 days, and divided into 4 groups: H/M-Sod2(+/-)+BSO, WT+BSO, H/M-Sod2(+/-)control, and WT control. The ventricular effective refractory period (ERP) and the monophasic action potential duration (MAPD) were determined. Levels of oxidative stress, potassium channel-related molecules, and K(+)channel-interacting protein-2 (KChIP2) were also evaluated. The H/M-Sod2(+/-)+BSO group exhibited markedly prolonged MAPD20, MAPD90 and ERP in comparison with the other groups (MAPD20: 14 ± 1 vs. 11 ± 1 ms, MAPD90: 77 ± 7 vs. 58 ± 4 ms, ERP: 61 ± 6 vs. 41 ± 3 ms, H/M-Sod2(+/-)+BSO vs. WT control; P<0.05). Mitochondrial superoxide and hydrogen peroxide formation in the myocardium increased in the H/M-Sod2(+/-)+BSO group in comparison with the WT+BSO group (P<0.05). Real-time RT-PCR and Western blotting revealed that Kv4.2 expression was downregulated in both BSO-treated groups, whereas KChIP2 expression was downregulated only in the H/M-Sod2(+/-)+BSO group (P<0.05).
  
  
  CONCLUSIONS
  BSO treatment caused hyperoxidative stress in the myocardium of H/M-Sod2(+/-)mice. Changes in the expression and function of potassium channels were considered to be involved in the mechanism of electrical remodeling in this model.
authors.affiliation: Department of Cardiovascular Medicine, Kitasato University School of Medicine.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Kurokawa
authors.forename: Shinichi
authors.initials: S
authors.lastname: Niwano
authors.forename: Hiroe
authors.initials: H
authors.lastname: Niwano
authors.forename: Masami
authors.initials: M
authors.lastname: Murakami
authors.forename: Shoko
authors.initials: S
authors.lastname: Ishikawa
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Masaki
authors.forename: Hideaki
authors.initials: H
authors.lastname: Tamaki
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Toda
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Noda
authors.forename: Takahiko
authors.initials: T
authors.lastname: Shimizu
authors.forename: Tohru
authors.initials: T
authors.lastname: Izumi
authors.forename: Junya
authors.initials: J
authors.lastname: Ako
mesh_terms: D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D015536:Down-Regulation; D006861:Hydrogen Peroxide / Q000378:metabolism; D051605:Kv Channel-Interacting Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac; D018384:Oxidative Stress; D051672:Shal Potassium Channels / Q000096:biosynthesis* / Q000235:genetics; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D000099156:Superoxide Dismutase 2
chemical_list: D000963:Antimetabolites; D019328:Buthionine Sulfoximine; D006861:Hydrogen Peroxide; D051605:Kv Channel-Interacting Proteins; D051672:Shal Potassium Channels; D013482:Superoxide Dismutase; D013481:Superoxides; D000099156:Superoxide Dismutase 2; C496755:Kcnip2 protein, mouse