Marionneau Céline, Brunet Sylvain, Flagg Thomas P, Pilgram Thomas K, Demolombe Sophie, Nerbonne Jeanne M
Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St Louis, MO 63110, USA.
Circ Res. 2008 Jun 6;102(11):1406-15. doi: 10.1161/CIRCRESAHA.107.170050. Epub 2008 May 1.
Left ventricular hypertrophy (LVH) is associated with electric remodeling and increased arrhythmia risk, although the underlying mechanisms are poorly understood. In the experiments here, functional voltage-gated (Kv) and inwardly rectifying (Kir) K(+) channel remodeling was examined in a mouse model of pressure overload-induced LVH, produced by transverse aortic constriction (TAC). Action potential durations (APDs) at 90% repolarization in TAC LV myocytes and QT(c) intervals in TAC mice were prolonged. Mean whole-cell membrane capacitance (C(m)) was higher, and I(to,f), I(K,slow), I(ss), and I(K1) densities were lower in TAC, than in sham, LV myocytes. Although the primary determinant of the reduced current densities is the increase in C(m), I(K,slow) amplitudes were decreased and I(ss) amplitudes were increased in TAC LV cells. Further experiments revealed regional differences in the effects of LVH. Cellular hypertrophy and increased I(ss) amplitudes were more pronounced in TAC endocardial LV cells, whereas I(K,slow) amplitudes were selectively reduced in TAC epicardial LV cells. Consistent with the similarities in I(to,f) and I(K1) amplitudes, Kv4.2, Kv4.3, and KChIP2 (I(to,f)), as well as Kir2.1 and Kir2.2 (I(K1)), transcript and protein expression levels were similar in TAC and sham LV. Unexpectedly, expression of I(K,slow) channel subunits Kv1.5 and Kv2.1 was increased in TAC LV. Biochemical experiments also demonstrated that, although total protein was unaltered, cell surface expression of TASK1 was increased in TAC LV. Functional changes in repolarizing K(+) currents with LVH, therefore, result from distinct cellular (cardiomyocyte enlargement) and molecular (alterations in the numbers of functional channels) mechanisms.
左心室肥厚（LVH）与电重构及心律失常风险增加相关，尽管其潜在机制尚不清楚。在本实验中，通过横断主动脉缩窄（TAC）建立压力超负荷诱导的LVH小鼠模型，研究了功能性电压门控（Kv）和内向整流（Kir）钾通道的重构情况。TAC组LV心肌细胞90%复极化时的动作电位时程（APD）和TAC组小鼠的QTc间期延长。与假手术组LV心肌细胞相比，TAC组的平均全细胞膜电容（C(m)）更高，I(to,f)、I(K,slow)、I(ss)和I(K1)密度更低。虽然电流密度降低的主要决定因素是C(m)的增加，但TAC组LV细胞中I(K,slow)幅度降低而I(ss)幅度增加。进一步实验揭示了LVH效应的区域差异。细胞肥大和I(ss)幅度增加在TAC组LV心内膜细胞中更明显，而I(K,slow)幅度在TAC组LV心外膜细胞中选择性降低。与I(to,f)和I(K1)幅度的相似性一致，TAC组和假手术组LV中Kv4.2、Kv4.3和KChIP2（I(to,f)）以及Kir2.1和Kir2.2（I(K1)）的转录和蛋白表达水平相似。出乎意料的是，TAC组LV中I(K,slow)通道亚基Kv1.5和Kv2.1的表达增加。生化实验还表明，虽然总蛋白未改变，但TAC组LV中TASK1的细胞表面表达增加。因此，LVH时复极化钾电流的功能变化是由不同的细胞机制（心肌细胞肥大）和分子机制（功能性通道数量改变）导致的。
