Published online before print May 1, 2008, doi: 10.1161/CIRCRESAHA.107.170050
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© 2008 American Heart Association, Inc.
Cellular Biology |
Distinct Cellular and Molecular Mechanisms Underlie Functional Remodeling of Repolarizing K+ Currents With Left Ventricular Hypertrophy
From the Departments of Molecular Biology and Pharmacology (C.M., S.B., J.M.N.), Cell Biology and Physiology (T.P.F.), and Radiology (T.K.P.), Washington University Medical School, St Louis, Mo; and INSERM U533, L’Institut du Thorax and Université de Nantes (S.D.), Faculté de Médecine, France. Present address for S.B.: Department of Pharmacology, University of Washington, Seattle.
Correspondence to Jeanne Nerbonne, Washington University School of Medicine, Molecular Biology and Pharmacology, 660 Euclid Ave, Box 8103, St Louis, MO 63110. E-mail jnerbonne{at}wustl.edu
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 QTc intervals in TAC mice were prolonged. Mean whole-cell membrane capacitance (Cm) was higher, and Ito,f, IK,slow, Iss, and IK1 densities were lower in TAC, than in sham, LV myocytes. Although the primary determinant of the reduced current densities is the increase in Cm, IK,slow amplitudes were decreased and Iss amplitudes were increased in TAC LV cells. Further experiments revealed regional differences in the effects of LVH. Cellular hypertrophy and increased Iss amplitudes were more pronounced in TAC endocardial LV cells, whereas IK,slow amplitudes were selectively reduced in TAC epicardial LV cells. Consistent with the similarities in Ito,f and IK1 amplitudes, Kv4.2, Kv4.3, and KChIP2 (Ito,f), as well as Kir2.1 and Kir2.2 (IK1), transcript and protein expression levels were similar in TAC and sham LV. Unexpectedly, expression of IK,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.
Key Words: hypertrophy • arrhythmia • heart failure
Related Article:
Circ. Res. 2008 102: 1298-1300.
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