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Overexpression of KCNJ2 in induced pluripotent stem cell-derived cardiomyocytes for the assessment of QT-prolonging drugs
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نویسنده
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li m. ,kanda y. ,ashihara t. ,sasano t. ,nakai y. ,kodama m. ,hayashi e. ,sekino y. ,furukawa t. ,kurokawa j.
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منبع
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journal of pharmacological sciences - 2017 - دوره : 134 - شماره : 2 - صفحه:75 -85
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چکیده
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Human induced pluripotent stem cell (hipsc)-derived cardiomyocytes hold great potentials to predict pro-arrhythmic risks in preclinical cardiac safety screening,although the hipsc cardiomyocytes exhibit rather immature functional and structural characteristics,including spontaneous activity. our physiological characterization and mathematical simulation showed that low expression of the inward-rectifier potassium (ik1) channel is a determinant of spontaneous activity. to understand impact of the low ik1 expression on the pharmacological properties,we tested if transduction of hipsc-derived cardiomyocytes with kcnj2,which encodes the ik1 channel,alters pharmacological response to cardiac repolarization processes. the transduction of kcnj2 resulted in quiescent hipsc-derived cardiomyocytes,which need pacing to elicit action potentials. significant prolongation of paced action potential duration in kcnj2-transduced hipsc-derived cardiomyocytes was stably measured at 0.1 μm e-4031,although the same concentration of e-4031 ablated firing of non-treated hipsc-derived cardiomyocytes. these results in single cells were confirmed by mathematical simulations. using the hipsc-derived cardiac sheets with kcnj2-transduction,we also investigated effects of a range of drugs on field potential duration recorded at 1 hz. the kcnj2 overexpression in hipsc-derived cardiomyocytes may contribute to evaluate a part of qt-prolonging drugs at toxicological concentrations with high accuracy. © 2017 the authors
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کلیدواژه
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Arrhythmias; Cardiac ion channels; Electrophysiology; iPS cells; Mathematical simulation; Potassium channels
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آدرس
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department of bio-informational pharmacology,tokyo medical and dental university,medical research institute,tokyo,113-8510, Japan, division of pharmacology,national institute of health sciences,tokyo,158-8501, Japan, department of cardiovascular medicine,shiga university of medical science,shiga,520-2192, Japan, department of biofunctional informatics,tokyo medical and dental university,tokyo,113-8510, Japan, institute for food sciences,hirosaki university,aomori,038-0012, Japan, department of bio-informational pharmacology,tokyo medical and dental university,medical research institute,tokyo,113-8510, Japan, department of bio-informational pharmacology,tokyo medical and dental university,medical research institute,tokyo,113-8510, Japan, division of pharmacology,national institute of health sciences,tokyo,158-8501,japan,laboratory of chemical pharmacology,graduate school of pharmaceutical sciences,university of tokyo,tokyo,113-0033, Japan, department of bio-informational pharmacology,tokyo medical and dental university,medical research institute,tokyo,113-8510, Japan, department of bio-informational pharmacology,tokyo medical and dental university,medical research institute,tokyo,113-8510,japan,department of bio-informational pharmacology,school of pharmaceutical sciences,university of shizuoka,shizuoka,422-8526, Japan
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Authors
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