Estrogen Contributes to Gender Differences in Mouse Ventricular Repolarization

RATIONALE:Fast-transient outward K (Ito,f) and ultrarapid delayed rectifier K currents (IK,slow, also known as IKur) contribute to mouse cardiac repolarization. Gender studies on these currents have reported conflicting results. OBJECTIVE:Key missing information in these studies is the estral stage of the animals. We revisited gender-related differences in K currents, taking into consideration the females’ estral stage. We hypothesized that changes in estrogen levels during the estral cycle could play a role in determining the densities of K currents underlying ventricular repolarization. METHODS AND RESULTS:Peak total K current (IK,total) densities (pA/pF, at +40 mV) were much higher in males (48.6±3.0) versus females at estrus (27.2±2.3) but not at diestrus-2 (39.1±3.4). Underlying this change, Ito,f and IK,slow were lower in females at estrus versus males and diestrus-2 (IK,slowmale 21.9±1.8, estrus 14.6±0.6, diestrus-2 20.3±1.4; Ito,fmale 26.8±1.9, estrus 14.9±1.6, diestrus-2 22.1±2.1). Lower IK,slow in estrus was attributable to only IK,slow1 reduction, without changes in IK,slow2. Estrogen treatment of ovariectomized mice decreased IK,total (46.4±3.0 to 28.4±1.6), Ito,f (26.6±1.6 to 12.8±1.0) and IK,slow (22.2±1.6 to 17.2±1.4). Transcript levels of Kv4.3 and Kv1.5 (underlying Ito,f and IK,slow, respectively) were lower in estrus versus diestrus-2 and male. In ovariectomized mice, estrogen treatment resulted in downregulation of Kv4.3 and Kv1.5 but not Kv4.2, KChIP2, or Kv2.1 transcripts. K current reduction in high estrogenic conditions were associated with prolongation of the action potential duration and corrected QT interval. CONCLUSION:Downregulation of Kv4.3 and Kv1.5 transcripts by estrogen are one mechanism defining gender-related differences in mouse ventricular repolarization.