Abstract
We recently reported the reduced ATP-sensitive potassium (KATP) channel activities in the transgenic mouse heart overexpressing the vascular type KATP channel pore-forming subunit (Kir6.1). Although dysfunction of cardiac KATP channel has been nominated as a cause of cardiomyopathy in human, these transgenic mice looked normal as wild-type (WT) during the experiment period (~20 weeks). Extended observation period revealed unexpected deaths beginning from 30 weeks and about 50% of the transgenic mice died by 55 weeks. Surface ECG recordings from the transgenic mice at rest demonstrated the normal sinus rhythm and the regular ECG complex as well as the control WT mice except for prolonged QT interval. However, the stress ECG test with noradrenaline revealed abnormal intraventricular conduction delay and arrhythmogeneity in the transgenic mouse. Fibrotic changes in the heart tissue were remarkable in aged transgenic mice, and the cardiac fibrosis developed progressively at least from the age of 30 weeks. Gene expression analyses revealed the differentiation of cardiac fibroblasts to myofibroblasts with elevated cytokine expressions was initiated way in advance before the fibrotic changes and the upregulation of BNP in the ventricle. In sum, Kir6.1TG mice provide an electro-pathological disease concept originated from KATP channel dysfunction.
Highlights
KATP channel (ATP-sensitive potassium channel) is a metabolic sensor channel which reflects changes in cell metabolism (ATP) into the electrophysiological membrane potential through the modulation of potassium ion flux[1]
We recently reported the downregulation of KATP channel in cardiomyocyte from the transgenic mouse overexpressing vascular form of KATP channel pore-forming subunit Kir6.1 driven by the α-myosin heavy chain (α-MHC) promoter[13]
Electrophysiological mechanisms causing J-ST segment changes need to employ further investigation, prolonged QT interval is supported by the lower density of sarcoplasmic KATP currents (IKATP), besides Ito, IK, and IK1
Summary
KATP channel (ATP-sensitive potassium channel) is a metabolic sensor channel which reflects changes in cell metabolism (ATP) into the electrophysiological membrane potential through the modulation of potassium ion flux[1]. In human hereditary genetic mutation has been pointed out as a cause of dilated cardiomyopathy and ischemic cardiomyopathy due to the loss of function of the KATP channel in cardiomyocytes[10,12]. These findings established a disease concept of ion-channel related cardiac dysfunction, cardiac channelopathy[4]. Further studies revealed that KATP current (IKATP) densities were significantly lower in Kir6.1TG than wild-type (WT) controls, as well as the voltage-dependent potassium currents such as Ito, IK, and IK1 This evidence might be explained as the dominant-negative effect of overexpressed Kir6.1 in the cardiac KATP channel in which Kir6.2 and SUR2A form a channel subunit[5]. The evidence that the KATP channel in the Kir6.1TG mouse heart does not function like WT led us to conduct the further investigation with extended observation period for more than a year to see the life expectancy of the Kir6.1TG mice
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