Circulation Journal
Online ISSN : 1347-4820
Print ISSN : 1346-9843
ISSN-L : 1346-9843
Molecular Cardiology
Cardiomyocyte-Derived Mitochondrial Superoxide Causes Myocardial Electrical Remodeling by Downregulating Potassium Channels and Related Molecules
Sayaka KurokawaShinichi NiwanoHiroe NiwanoMasami MurakamiShoko IshikawaYoshihiko MasakiHideaki TamakiToshihiko TodaYoshihiro NodaTakahiko ShimizuTohru IzumiJunya Ako
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Supplementary material

2014 Volume 78 Issue 8 Pages 1950-1959

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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).Methods and 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, MAPD90and 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. (Circ J 2014; 78: 1950–1959)

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© 2014 2013 THE JAPANESE CIRCULATION SOCIETY
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