Cardiomyocyte-Derived Mitochondrial Superoxide Causes Myocardial Electrical Remodeling by Downregulating Potassium Channels and Related Molecules

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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.