Redox regulation of Ito remodeling in diabetic rat heart.

摘要

Oxidative stress and the resulting change in cell redox state are proposed to contribute to pathogenic alterations in ion channels that underlie electrical remodeling of the diseased heart. The present study examined whether K(+) channel remodeling is controlled by endogenous oxidoreductase systems that regulate redox-sensitive cell functions. Diabetes was induced in rats by streptozotocin, and experiments were conducted after 3-5 wk of hyperglycemia. Spectrophotometric assays of ventricular tissue extracts from diabetic rat hearts revealed divergent changes in two major oxidoreductase systems. The thioredoxin (TRX) system in diabetic rat heart was characterized by a 52% decrease in TRX reductase (TRXR) activity from control heart (P < 0.05), whereas TRX activity was 1.7-fold greater than control heart (P < 0.05). Diabetes elicited similar changes in the glutaredoxin (GRX) system: glutathione reductase was decreased 35% from control level (P < 0.05), and GRX activity was 2.5-fold greater than in control heart (P < 0.05). The basal activity of glucose-6-phosphate dehydrogenase, which generates NADPH required by the TRX and GRX systems, was not altered by diabetes. Voltage-clamp studies showed that the characteristically decreased density of the transient outward K(+) current (I(to)) in isolated diabetic rat myocytes was normalized by in vitro treatment with insulin (0.1 microM) or the metabolic activator dichloroacetate (1.5 mM). The effect of these agonists on I(to) was blocked by inhibitors of glucose-6-phosphate dehydrogenase. Moreover, inhibitors of TRXR, which controls the reducing activity of TRX, also blocked upregulation of I(to) by insulin and dichloroacetate. These data suggest that K(+) channels underlying I(to) are regulated in a redox-sensitive manner by the TRX system and the remodeling of I(to) that occurs in diabetes may be due to decreased TRXR activity. We propose that oxidoreductase systems are an important repair mechanism that protects ion channels and associated regulatory proteins from irreversible oxidative damage.