Program

PO2-3-40

Kir6.1 transgenic mice for the analyses of cardiac channelopathy

[Speaker] Akio Matsumoto:1
[Co-author] Yasuhiro Watanabe:1, Takashi Kishimoto:2, Haruaki Nakaya:1
1:Department of Pharmacology, Chiba University, Graduate School of Medicine, Japan, 2:Department of Molecular Pathology, Chiba University, Graduate School of Medicine, Japan

 KATP channel is a metabolic sensor linking cellular metabolic state (ATP/ADP ratio) to membrane excitability. In cardiomyocytes, KATP channel plays a cardioprotective role during the anoxic condition such as coronary occlusion by increasing membrane K+ currents, which then inhibits the excessive influx and accumulation of Ca2+ by shortening the action potential duration. The sarcolemmal KATP channels in ventricular myocytes are composed primarily of Kir6.2 and SUR2A subunits whereas KATP channels in vascular smooth muscle cells are predominantly composed of Kir6.1 and SUR2B.
 We recently reported the downregulation of cardiac KATP channel from the transgenic mouse specifically overexpressing Kir6.1 in cardiomyocyte. The transgenic mouse strains (termed as Kir6.1TG) showed the prolonged QT interval, which was supported by the extended action potential duration by electrophysiological analyses with the patch-clamp techniques. Further studies revealed that KATP current densities were significantly lower in Kir6.1TG than 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.
 The Kir6.1TG mice revealed unexpected deaths beginning from 30 wks and died significantly earlier with the median survival between 52 to 55 wks of age than non-transgenic WT control (more than 95% of WT mice survived longer than 80 wks). Cardiac tissue fibrosis was remarkable, and the stress ECG test with noradrenaline revealed abnormal intraventricular conduction delay and arrhythmogenicity. Gene-expression profiles support low KATP channel expressions, progressive development of fibrosis and mild cardiac failure.
 In human hereditary genetic mutation has been pointed out as a cause of dilated cardiomyopathy and ischemic cardiomyopathy due to the dysfunction of the cardiac KATP channel, and the disease was termed as cardiac channelopathy. Since the genetic ablation brings complete loss of function, the knock-out model does not mimic the pathological status of KATP channelopathy. On the contrary, ectopic overexpression of Kir6.1 in cardiomyocyte provides a suitable animal model for the analyses of the disease and the development of therapeutics for human cardiac channelopathy.
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