title: Restoring depressed HERG K+ channel function as a mechanism for insulin treatment of abnormal QT prolongation and associated arrhythmias in diabetic rabbits.
abstract: 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 (IKr) was markedly reduced in IDDM hearts, and hyperglycemia depressed the function of the human ether-a-go-go-related gene (HERG), which conducts IKr. 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 IKr/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 IKr/HERG as a potential therapeutic target for treatment of the disorder.
authors.affiliation: Research Center, Montreal Heart Institute, 5000 Belanger East, Montreal, PQ, Canada H1T 1C8.
authors.forename: Yiqiang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jiening
authors.initials: J
authors.lastname: Xiao
authors.forename: Huizhen
authors.initials: H
authors.lastname: Wang
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Luo
authors.forename: Jingxiong
authors.initials: J
authors.lastname: Wang
authors.forename: Louis R
authors.initials: LR
authors.lastname: Villeneuve
authors.forename: Haiqing
authors.initials: H
authors.lastname: Zhang
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Bai
authors.forename: Baofeng
authors.initials: B
authors.lastname: Yang
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Wang
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D003925:Diabetic Angiopathies / Q000188:drug therapy / Q000503:physiopathology* / Q000517:prevention & control; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects / Q000502:physiology*; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007328:Insulin / Q000494:pharmacology* / Q000627:therapeutic use; D008133:Long QT Syndrome / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D008297:Male; D018384:Oxidative Stress / Q000502:physiology; D011817:Rabbits
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D007004:Hypoglycemic Agents; D007328:Insulin