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(Circulation Research. 2009;105:343.)
© 2009 American Heart Association, Inc.

Integrative Physiology

Estrogen Contributes to Gender Differences in Mouse Ventricular Repolarization

Tomoaki Saito, Andrea Ciobotaru, Jean Chrisostome Bopassa, Ligia Toro, Enrico Stefani, Mansoureh Eghbali

From the Department of Anesthesiology (T.S., A.C., J.C.B., L.T., E.S., M.E.), Division of Molecular Medicine; Departments of Molecular & Medical Pharmacology (L.T.) and Physiology (E.S.); and Brain Research Institute (L.T., E.S.), David Geffen School of Medicine at University of California Los Angeles. Present address for T.S.: Medical Science Division, Japan Patent Office, Ministry of Economy, Trade and Industry, Tokyo, Japan.

Correspondence to Dr Mansoureh Eghbali, UCLA School of Medicine, Department of Anesthesiology, BH-160CHS, Los Angeles, CA 90095-7115. E-mail meghbali{at}ucla.edu

Rationale: Fast-transient outward K⁺ (I_to,f) and ultrarapid delayed rectifier K⁺ currents (I_K,slow, also known as I_Kur) 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 (I_K,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, I_to,f and I_K,slow were lower in females at estrus versus males and diestrus-2 (I_K,slow: male 21.9±1.8, estrus 14.6±0.6, diestrus-2 20.3±1.4; I_to,f: male 26.8±1.9, estrus 14.9±1.6, diestrus-2 22.1±2.1). Lower I_K,slow in estrus was attributable to only I_K,slow1 reduction, without changes in I_K,slow2. Estrogen treatment of ovariectomized mice decreased I_K,total (46.4±3.0 to 28.4±1.6), I_to,f (26.6±1.6 to 12.8±1.0) and I_K,slow (22.2±1.6 to 17.2±1.4). Transcript levels of Kv4.3 and Kv1.5 (underlying I_to,f and I_K,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.

Key Words: estrogen • I_to,f • I_K,slow • estrus • diestrus • gender • Kv4.3 • Kv1.5