Restoring depressed HERG K+ channel function as a mechanism for insulin treatment of abnormal QT prolongation and associated arrhythmias in diabetic rabbits.
Restoring depressed HERG K+ channel function as a mechanism for insulin treatment of abnormal QT prolongation and associated arrhythmias in diabetic rabbits.
复制标题
恢复抑制的 HERG K 通道功能作为胰岛素治疗糖尿病兔异常 QT 延长和相关心律失常的机制。
DOI：
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发表时间：
2006
期刊：
影响因子：
--
通讯作者：
Zhiguo Wang
中科院分区：
文献类型：
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作者：
Yiqiang Zhang;Jiening Xiao;Hui;Xiaobin Luo;Jingxiong Wang;L. Villeneuve;Haiqing Zhang;Yunlong Bai;Baofeng Yang;Zhiguo Wang
糖尿病患者QT间期异常延长（QT-P）增加了致死性室性心律失常的风险，已成为一个不容忽视的临床问题，并引起了基础科学家的越来越多的关注。QT-P校正可能是减少糖尿病患者心源性猝死的重要措施。在此，我们报告了胰岛素在预防QT-P和相关心律失常中的功效，以及在1型胰岛素依赖性糖尿病（IDDM）家兔模型中的作用机制。心率校正的QT（QTc）间期和动作电位时程显著延长，伴有频繁的室性心动过速。快速延迟整流钾电流（IKr）在胰岛素依赖型糖尿病心脏中显著降低，高血糖抑制了人类ether-a-go-go-related基因（HERG）的功能，该基因传导IKr。损伤主要归因于心肌氧化损伤的增强，如细胞内活性氧水平的增加和同时内源性抗氧化储备的减少以及脂质过氧化和蛋白质氧化的增加所示。此外，IDDM或高血糖导致HERG蛋白水平下调。胰岛素可恢复受抑制的IKr/HERG，并防止QTc/动作电位时程延长和相关心律失常，胰岛素的有益作用部分归因于其抗氧化能力。我们的研究代表了氧化应激作为HERG K+功能障碍的主要代谢机制的第一个文件，这导致糖尿病QT-P，并建议IKr/HERG作为治疗该疾病的潜在治疗靶点。
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.
胰岛素和谷胱甘肽上调糖尿病大鼠心室肌细胞中 K( ) 通道。
影响因子：
10.8
作者：
Xu,Zhi;Patel,KaushikP;Lou,MarjorieF;Rozanski,GeorgeJ
通讯作者：
Rozanski,GeorgeJ
影响因子：
4.4
作者：
Pearson, WR;Wood, T;Miller, W
通讯作者：
Miller, W
影响因子：
20.1
作者：
Wymore, RS;Gintant, GA;Cohen, IS
通讯作者：
Cohen, IS