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/MSod2+/-) 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, 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.