Abstract 1072: Distinct Cellular And Molecular Mechanisms Underlie K+ Current Remodeling In Left Ventricular Hypertrophy
Left Ventricular Hypertrophy (LVH) is associated with electrical remodeling and increased risk of lethal ventricular arrhythmias, although the underlying molecular mechanisms are poorly understood. A mouse model of pressure overload-induced LVH was exploited to explore directly the relationship(s) between molecular and functional remodeling of repolarizing voltage-gated (Kv) and inwardly rectifying (Kir) K+ channels with LVH. Pressure overload was induced by transverse aortic constriction (TAC) and confirmed by echocardiography, and experiments were conducted 7 days after surgery. Mean ± SEM cell membrane capacitance (Cm) was significantly (P<.001) higher in TAC (172±5 pF; n=70), than in sham (132±3 pF; n=73), LV cells; and peak Kv current, Ito,f, IK,slow, Iss and IK1 densities were significantly (P<.001) lower in TAC LV myocytes. In addition, action potential durations at 90% repolarization were prolonged in TAC LV myocytes. In parallel with the reductions in current densities, the transcript and protein expression levels of the Ito,f (Kv4.2) and IK1 (Kir2.1) pore-forming α subunits, as well as the Ito,f accessory subunit KChIP2, were markedly reduced in TAC, compared with sham, LV. In contrast, expression of the Kv α subunits encoding IK,slow (Kv1.5, Kv2.1) and of the putative Kv1.5 channel regulatory protein, SAP-97, in sham and TAC LV were not different. Further experiments, however, revealed marked regional differences in the effects of LVH. Cellular hypertrophy, for example, was significantly (P<.05) more pronounced in endocardial (ENDO), than in epicardial (EPI), TAC LV myocytes with mean ± SEM Cm values of 215±11 pF; n=18 and 177±9 pF; n=23, respectively, and the reductions in Kv and Kir current densities in ENDO cells reflect only the increase in Cm. In TAC EPI cells, however, mean ± SEM IK,slow amplitude (1167±107 pA; n=23) was significantly (P<.001) lower than in sham EPI cells (3031±193 pA; n=13), resulting in a much larger decrease in IK,slow densities in TAC EPI, than ENDO, cells and a collapse of the normal transmural gradient in IK,slow and peak Kv current densities. Taken together, these results reveal that distinct cellular and molecular (transcriptional and post-translational) mechanisms underlie Kv and Kir current remodeling in LVH.