Abstract

Hyperglycemia and hypoglycemia both can cause prolongation of the Q-T interval and ventricular arrhythmias. Here we studied modulation of human ether-à-go-go-related gene (HERG) K(+) channel, the major molecular component of delayed rectifier K(+) current responsible for cardiac repolarization, by glucose in HEK293 cells using whole-cell patch clamp techniques. We found that both hyperglycemia (extracellular glucose concentration [Glu](o) = 10 or 20 mm) and hypoglycemia ([Glu](o) = 2.5, 1, or 0 mm) impaired HERG function by reducing HERG current (I(HERG)) density, as compared with normoglycemia ([Glu](o) = 5 mm). Complete inhibition of glucose metabolism (glycolysis and oxidative phosphorylation) by 2-deoxy-d-glucose mimicked the effects of hypoglycemia, but inhibition of glycolysis or oxidative phosphorylation alone did not cause I(HERG) depression. Depletion of intracellular ATP mimicked the effects of hypoglycemia, and replacement of ATP by GTP or non-hydrolysable ATP failed to prevent the effects. Inhibition of oxidative phosphorylation by NaCN or application of antioxidants vitamin E or superoxide dismutase mimetic (Mn(III) tetrakis(4-benzoic acid) porphyrin chloride) abrogated and incubation with xanthine/xanthine oxidase mimicked the effects of hyperglycemia. Hyperglycemia or xanthine/xanthine oxidase markedly increased intracellular levels of reactive oxygen species, as measured by 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate (CM-H(2)DCFDA) fluorescence dye, and this increase was prevented by NaCN, vitamin E, or Mn(III) tetrakis(4-benzoic acid) porphyrin chloride. We conclude that ATP, derived from either glycolysis or oxidative phosphorylation, is critical for normal HERG function; depression of I(HERG) in hypoglycemia results from underproduction of ATP and in hyperglycemia from overproduction of reactive oxygen species. Impairment of HERG function might contribute to Q-T prolongation caused by hypoglycemia and hyperglycemia.

Highlights

  • Hyperglycemia and hypoglycemia both can cause prolongation of the Q-T interval and ventricular arrhythmias

  • Such an experimental design allowed us to study the effect of Glu on impaired HERG function by reducing HERG current (IHERG) under conditions devoid of influence from exogenous ATP included in the pipette, which is an important issue to be described later

  • Role of reactive oxygen species (ROS) on Hyperglycemia-induced IHERG Depression— Collectively from the above experiments, glucose metabolism is necessary for maintaining the human ether-a -gogo-related gene (HERG) channel function, and the ATP produced by either glycolysis or oxidative phosphorylation seems to be a key factor for the regulation; on the other hand, the fact that NaCN restores the depressed IHERG induced by 20

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Summary

SIMILAR PHENOTYPES BUT DIFFERENT MECHANISMS*

From the ‡Research Center, Montreal Heart Institute, Montreal, Quebec H1T 1C8, the §Department of Medicine, University of Montreal, Montreal, Quebec H3C 3J7, Canada and the ʈDepartment of Pharmacology, Harbin Medical University, Harbin, Heilongjiang 150086, Peoples Republic of China Hyperglycemia and hypoglycemia both can cause prolongation of the Q-T interval and ventricular arrhythmias. It is conceivable that HERG alteration might be involved in the Q-T prolongation induced by hyperglycemia and hypoglycemia This thought prompted us to carry out a series of experiments to study the effects of glucose on HERG Kϩ channels and the potential mechanisms

EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
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