Estrogen contributes to gender differences in mouse ventricular repolarization.
BACKGROUND
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.


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,slow)(1) reduction, without changes in I(K,slow)(2). 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.


CONCLUSIONS
Downregulation of Kv4.3 and Kv1.5 transcripts by estrogen are one mechanism defining gender-related differences in mouse ventricular repolarization.
Saito
Tomoaki
T
Department of Anesthesiology, Division of Molecular Medicine, David Geffen School of Medicine at University of California Los Angeles, CA 90095-7115, USA.
Ciobotaru
Andrea
A
Bopassa
Jean Chrisostome
JC
Toro
Ligia
L
Stefani
Enrico
E
Eghbali
Mansoureh
M
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D004967:Estrogens / Q000378:metabolism / Q000494:pharmacology*; D030762:Estrous Cycle / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism*; D051605:Kv Channel-Interacting Proteins / Q000096:biosynthesis; D008297:Male; D051379:Mice; D011188:Potassium / Q000378:metabolism*; D012727:Sex Characteristics; D051637:Shaker Superfamily of Potassium Channels / Q000096:biosynthesis
D004967:Estrogens; C496755:Kcnip2 protein, mouse; D051605:Kv Channel-Interacting Proteins; D051637:Shaker Superfamily of Potassium Channels; D011188:Potassium