Submitted on December 21, 2005
Accepted on April 3, 2006
Restoring depressed HERG K+ channel function as a mechanism for insulin treatment of the abnormal QT prolongation in diabetic rabbits
Yiqiang Zhang1, Jiening Xiao2, Huizhen Wang2, Xiaobin Luo1, Jingxiong Wang2, Louis R. Villeneuve2, Haiqing Zhang2, Yunlong Bai3, Baofeng Yang4, and Zhiguo Wang5*
1 Department of Medicine, University of Montreal, Montreal, Canada; Research Center, Montreal Heart Institute, Montreal, Canada
2 Research Center, Montreal Heart Institute, Montreal, Canada
3 Department of Pharmacology, Harbin Medical University, Harbin, China
4 Department of Pharmacology, Harbin Medical University, Harbin, China; Institute of Cardiovascular Researc, Harbin Medical University, Harbin, China
5 Department of Medicine, University of Montreal, Montreal, Canada; Research Center, Montreal Heart Institute, Montreal, Canada; Institute of Cardiovascular Researc, Harbin Medical University, Harbin, China
* To whom correspondence should be addressed. E-mail: wz.email{at}gmail.com.
Abnormal QT prolongation (QT-P) in diabetic patients has become a non-negligible clinical problem and attracted increasing attention from basic scientists, due to its resultant increases in the risk of lethal ventricular arrhythmias. Correction of QT-P may be an important measure in minimizing sudden cardiac death in diabetic patients. Herein 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 I insulin-dependent diabetes mellitus (IDDM). The heart rate-corrected QT interval (QTc interval) and action potential duration (APD) were considerably prolonged with frequent occurrence of ventricular tachycardias. The rapid delayed rectifier K+ current (IKr) was markedly reduced in IDDM hearts and hyperglycemia depressed the function of HERG that conducts IKr. The impairment was primarily ascribed to the enhanced oxidative damages 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 IKr/HERG and prevented QTc/APD prolongation and the associated arrhythmias and the beneficial actions of insulin are partially due to its anti-oxidant ability. Our study represents the first documentation of oxidative stress as the major metabolic mechanism for HERG K+ dysfunction that causes diabetic QT prolongation and suggests IKr/HERG as a potnetial therapeutic target for the treatment of the disorder.
