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Transgenic upregulation of I sub(K1) in the mouse heart leads to multiple abnormalities of cardiac excitability
To assess the functional significance of upregulation of the cardiac current (I sub(K1)), we have produced and characterized the first transgenic (TG) mouse model of I sub(K1) upregulation. To increase I sub(K1) density, a pore-forming subunit of the Kir2.1 (green fluorescent protein-tagged) channel...
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Published in: | American journal of physiology. Heart and circulatory physiology 2004-12, Vol.287 (6), p.H2790-H2802 |
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Main Authors: | , , |
Format: | Article |
Language: | English |
Online Access: | Get full text |
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Summary: | To assess the functional significance of upregulation of the cardiac current (I sub(K1)), we have produced and characterized the first transgenic (TG) mouse model of I sub(K1) upregulation. To increase I sub(K1) density, a pore-forming subunit of the Kir2.1 (green fluorescent protein-tagged) channel was expressed in the heart under control of the alpha -myosin heavy chain promoter. Two lines of TG animals were established with a high level of TG expression in all major parts of the heart: line 1 mice were characterized by 14% heart hypertrophy and a normal life span; line 2 mice displayed an increased mortality rate, and in mice 100%. In adult ventricular myocytes expressing the Kir2.1-GFP subunit, I sub(K1) conductance at the reversal potential was increased -9- and -10-fold in lines 1 and 2, respectively. Expression of the Kir2.1 transgene in line 2 ventricular myocytes was heterogeneous when assayed by single-cell analysis of GFP fluorescence. Surface ECG recordings in line 2 mice revealed numerous abnormalities of excitability, including slowed heart rate, premature ventricular contractions, atrioventricular block, and atrial fibrillation. Line 1 mice displayed a less severe phenotype. In both TG lines, action potential duration at 90% repolarization and monophasic action potential at 75-90% repolarization were significantly reduced, leading to neuronlike action potentials, and the slow phase of the T wave was abolished, leading to a short Q-T interval. This study provides a new TG model of I sub(K1) upregulation, confirms the significant role of I sub(K1) in cardiac excitability, and is consistent with adverse effects of I sub(K1) upregulation on cardiac electrical activity. |
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ISSN: | 0363-6135 1522-1539 |