Transgenic upregulation of I K1 in the mouse heart leads to multiple abnormalities of cardiac excitability

• Published in: American journal of physiology. Heart and circulatory physiology 2004-12, Vol.287 (6), p.H2790-H2802
• Main Authors: Li, Jingdong, McLerie, Meredith, Lopatin, Anatoli N.
• Format: Article
• Language: English
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00114.2004

To assess the functional significance of upregulation of the cardiac current ( I K1 ), we have produced and characterized the first transgenic (TG) mouse model of I K1 upregulation. To increase I K1 density, a pore-forming subunit of the Kir2.1 (green fluorescent protein-tagged) channel was expressed in the heart under control of the α-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 ≤1 mo old, heart weight-to-body weight ratio was increased by >100%. In adult ventricular myocytes expressing the Kir2.1-GFP subunit, I 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 K1 upregulation, confirms the significant role of I K1 in cardiac excitability, and is consistent with adverse effects of I K1 upregulation on cardiac electrical activity.