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This Article Full Text Full Text (PDF) All Versions of this Article: 291/3/H1446    most recent 01356.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Zhang, Y. Articles by Wang, Z. Search for Related Content PubMed PubMed Citation Articles by Zhang, Y. Articles by Wang, Z.

Restoring depressed HERG K⁺ channel function as a mechanism for insulin treatment of abnormal QT prolongation and associated arrhythmias in diabetic rabbits

¹Research Center, Montreal Heart Institute; ²Department of Medicine, University of Montreal, Montreal, Quebec, Canada; ³Department of Pharmacology (State-Province Key Laboratory of China), and ⁴Institute of Cardiovascular Research, Harbin Medical University, Harbin, Heilongjiang, People's Republic of China

Submitted 21 December 2005 ; accepted in final form 3 April 2006

Abnormal QT prolongation (QT-P) in diabetic patients has become a nonnegligible clinical problem and has attracted increasing attention from basic scientists, because it increases the risk of lethal ventricular arrhythmias. Correction of QT-P may be an important measure in minimizing sudden cardiac death in diabetic patients. Here we report the efficacy of insulin in preventing QT-P and the associated arrhythmias and the mechanisms underlying the effects in a rabbit model of type 1 insulin-dependent diabetes mellitus (IDDM). The heart rate-corrected QT (QTc) interval and action potential duration were considerably prolonged, with frequent ventricular tachycardias. The rapid delayed rectifier K⁺ current (I_Kr) was markedly reduced in IDDM hearts, and hyperglycemia depressed the function of the human ether-a-go-go-related gene (HERG), which conducts I_Kr. The impairment was primarily ascribed to the enhanced oxidative damage to the myocardium, as indicated by the increased intracellular level of reactive oxygen species and simultaneously decreased endogenous antioxidant reserve and by the increased lipid peroxidation and protein oxidation. Moreover, IDDM or hyperglycemia resulted in downregulation of HERG protein level. Insulin restored the depressed I_Kr/HERG and prevented QTc/action potential duration prolongation and the associated arrhythmias, and the beneficial actions of insulin are partially due to its antioxidant ability. Our study represents the first documentation of oxidative stress as the major metabolic mechanism for HERG K⁺ dysfunction, which causes diabetic QT-P, and suggests I_Kr/HERG as a potential therapeutic target for treatment of the disorder.

diabetes; cardiovascular disease; insulin-dependent diabetes mellitus; action potential duration

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