Distinct Cellular and Molecular Mechanisms Underlie Functional Remodeling of Repolarizing K + Currents With Left Ventricular Hypertrophy

Abstract

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.