Distinct cellular and molecular mechanisms underlie functional remodeling of repolarizing K+ currents with left ventricular hypertrophy.
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.
Marionneau
Céline
C
Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St Louis, MO 63110, USA.
Brunet
Sylvain
S
Flagg
Thomas P
TP
Pilgram
Thomas K
TK
Demolombe
Sophie
S
Nerbonne
Jeanne M
JM
D000818:Animals; D015153:Blotting, Western; D002469:Cell Separation; D004195:Disease Models, Animal; D004452:Echocardiography; D020869:Gene Expression Profiling; D017379:Hypertrophy, Left Ventricular / Q000000981:diagnostic imaging / Q000378:metabolism*; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism*; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D012313:RNA / Q000378:metabolism
D015221:Potassium Channels; D012313:RNA; D011188:Potassium