Redox imbalance elicited by oxidative stress contributes to pathogenic remodeling of ion channels that underlies arrhythmogenesis and contractile dysfunction in the failing heart. This study examined whether expression of K⁺ channels in the remodeled ventricle is controlled by the thioredoxin system, a principal oxidoreductase network regulating redox-sensitive proteins. Ventricular dysfunction was induced in rats by coronary artery ligation and experiments were conducted 6-8 wk post-infarction. Biochemical assays of tissue extracts from infarcted hearts showed that thioredoxin reductase activity was decreased 32% from sham controls (p<0.05), whereas thioredoxin activity was 51% higher post-infarction (p<0.05). These differences paralleled changes in protein abundance as determined by Western blot. However, whereas real-time PCR showed thioredoxin reductase mRNA to be significantly decreased post-infarction, thioredoxin mRNA was not altered. In voltage-clamp studies of myocytes from infarcted hearts, the characteristic down-regulation of transient outward K⁺ current density was reversed by exogenous pyruvate and this effect was blocked by specific inhibitors of the thioredoxin system: auranofin or 13-cis-retinoic acid. Real-time PCR and Western blot analyses of myocyte suspensions from infarcted hearts showed that pyruvate increased mRNA and protein abundance of Kv4.2 and Kv4.3 channel -subunits as well as the accessory protein KChIP2 when compared with time-matched, untreated cells (p<0.05). The pyruvate-induced increase in Kv4.x expression was blocked by auranofin but up-regulation of KChIP2 expression was not affected. These data suggest that expression of Kv4.x channels is redox-regulated by the thioredoxin system which may be a novel therapeutic target to reverse or limit electrical remodeling of the failing heart.