Transgenic upregulation ofI_K1in the mouse heart leads to multiple abnormalities of cardiac excitability

Abstract

To assess the functional significance of upregulation of the cardiac current (IK1), we have produced and characterized the first transgenic (TG) mouse model of IK1 upregulation. To increase IK1 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 < or =1 mo old, heart weight-to-body weight ratio was increased by >100%. In adult ventricular myocytes expressing the Kir2.1-GFP subunit, IK1 conductance at the reversal potential was increased approximately 9- and approximately 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 IK1 upregulation, confirms the significant role of IK1 in cardiac excitability, and is consistent with adverse effects of IK1 upregulation on cardiac electrical activity.

Evidence for Activity-Dependent Cortical Wiring: Formation of Interhemispheric Connections in Neonatal Mouse Visual Cortex Requires Projection Neuron Activity

“…To our knowledge, the present study is the first to reveal the possibility that patients carrying a mutation in Kir2.1 may have deficits in cortical connectivity. Overexpression of wild-type Kir2.1 in the heart induces multiple abnormalities in cardiac excitability (Miake et al, 2003;Li et al, 2004). Our findings suggest that enhanced Kir2.1 channel activity through overexpression of wild-type channels or gain-of-function mutant channels is also detrimental to the formation of interhemispheric connections in the brain.…”

Newly Identified NO‐Sensor Guanylyl Cyclase/Connexin 43 Association Is Involved in Cardiac Electrical Function

“…B, ECG trace showing scales and parameters used in the analysis (P‐wave duration, QRS duration, and QT‐corrected [QTc] interval). QRS duration was defined as in the study by Li et al28 and evaluates progression of depolarization. An isoelectrical level was used to determine the beginning of the T wave.…”

IK1 and cardiac hypoxia: After the long and short QT syndromes, what else can go wrong with the inward rectifier K+ currents?

“…Increased density of I K1 was also observed to be associated with other abnormalities, such as junctional escape, atrioventricular block, AF, cardiac hypertrophy, and death in the transgenic animals [11].…”

“…Using a transgenic mouse model, cardiac specific over-expression of Kir2.1 subunits resulting in the up-regulation of I K1 leads to multiple abnormalities of cardiac excitability, including marked shortening in APD and effective refractory period (ERP), and nearcomplete elimination of the slow T wave, with a short QT interval [11]. Increased density of I K1 was also observed to be associated with other abnormalities, such as junctional escape, atrioventricular block, AF, cardiac hypertrophy, and death in the transgenic animals [11].…”

“…important roles of I K1 in cardiac physiology have long been documented, its roles in cardiac arrhythmia generation have only been increasingly recognized recently [6][7][8][9][10][11][12] and indeed, have "lagged" behind other K + channels, e.g., KvLQT1 (encoded by KCNQ1 gene) and HERG (encoded by KCNH2 gene) which have been linked to several types of inherited cardiac arrhythmias and drug-induced long QT syndrome [13,14]. The article by Piao et al, in this issue of the Journal provides compelling evidence for yet another role of I K1 , namely as a "first responder" during cardiac ischemia and hypoxia [15].…”