Redox regulation of I to remodeling in diabetic rat heart

Xun Li, Zhi Xu, Shumin Li, George J. Rozanski

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

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 μM) 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.

Original languageEnglish (US)
Pages (from-to)H1417-H1424
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume288
Issue number3 57-3
DOIs
StatePublished - Mar 1 2005

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Thioredoxins
Oxidation-Reduction
Glutaredoxins
Oxidoreductases
Glucosephosphate Dehydrogenase
Ion Channels
Atrial Remodeling
Insulin
Thioredoxin-Disulfide Reductase
Tissue Extracts
Glutathione Reductase
Streptozocin
NADP
Hyperglycemia
Muscle Cells
Heart Diseases
Oxidative Stress
Up-Regulation
Proteins

Keywords

  • Glutaredoxin
  • Insulin
  • Potassium
  • Thioredoxin
  • Transient outward current

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Redox regulation of I to remodeling in diabetic rat heart . / Li, Xun; Xu, Zhi; Li, Shumin; Rozanski, George J.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 288, No. 3 57-3, 01.03.2005, p. H1417-H1424.

Research output: Contribution to journalArticle

Li, Xun ; Xu, Zhi ; Li, Shumin ; Rozanski, George J. / Redox regulation of I to remodeling in diabetic rat heart In: American Journal of Physiology - Heart and Circulatory Physiology. 2005 ; Vol. 288, No. 3 57-3. pp. H1417-H1424.
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AB - 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 μM) 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.

KW - Glutaredoxin

KW - Insulin

KW - Potassium

KW - Thioredoxin

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