Estrogen Contributes to Gender Differences in Mouse Ventricular Repolarization

Abstract

Rationale Fast-transient outward K+ (Ito,f) and ultra-rapid delayed rectifier K+ currents (IKur or IK,slow) contribute to mouse cardiac repolarization. Gender studies on these currents have reported conflicting results. Objective One key missing piece information in these studies is the animals’ estral stage. We decided to revisit gender-related differences in K+ currents, taking into consideration the females’ estral stage. Methods and Results 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. Peak total K+ current (IK,total) densities (pA/pF, at +40 mV) were much higher in males (48.6±3.0) than in 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 vs males and diestrus-2 (IK,slow: male 21.9±1.8, estrus 14.6±0.6, diestrus-2 20.3±1.4; Ito,f: male 26.8±1.9, estrus 14.9±1.6, diestrus-2 22.1±2.1). The lower IK,slow in estrus was only due to IK,slow1 reduction without changes of 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 vs. diestrus-2 and male. In ovariectomized mice, estrogen treatment resulted in downregulation of Kv4.3 and Kv1.5, but not Kv4.2, KChIP2 and 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.

Sex Hormones and the QT Interval: A Review

“…Endogenous testosterone and progesterone shorten the action potential, 8,9,11 and estrogen lengthens the QTc interval in animals. 10 These effects occur through alterations in myocardial I Ca,L , I Kr , I Ks and I K1 channels, which control phases 2 and 3 of the cardiac action potential. Exogenous ET lengthens the QTc interval, and EPT has no effect.…”

“…Saito et al 10 compared the QTc of mice with high endogenous estrogen to the QTc of ovariectomized mice with no detectable endogenous estrogen. They found a significantly shorter QTc in the ovariectomized group ( p < 0.05).…”

“…[6][7][8][9][10][11] Endogenous testosterone and progesterone shorten the action potential 8,9,11 and estrogen lengthens the QT interval in animals. 10 During a single menstrual cycle, progesterone levels but not estrogen levels have the dominant effect on ventricular repolarization in women. 8,9 Studies of menopause hormone therapy (MHT) in the form of estrogen-alone therapy (ET) and estrogen plus progesterone therapy (EPT) have suggested a counterbalancing effect of exogenous estrogen and progesterone on the QT.…”

Regulation of the Female Rat Estrous Cycle by a Neural Cell-Specific Epidermal Growth Factor-like Repeat Domain Containing Protein, NELL2

“…We found that the expression of NELL2 mRNA peaked at the proestrous phase, when circulating E2 concentrations are high- est (Saito et al, 2009). This finding is consistent with the results of our previous studies showing that E2 activates NELL2 transcription (Choi et al, 2010) and that NELL2 is expressed in the ERα expressing hypothalamic cells (Choi et al, 2010;Jeong et al, 2008a).…”

PDE5 inhibitor efficacy is estrogen dependent in female heart disease

“…We observed similar additive beneficial effects of E2 and sildenafil treatments in male pressure-overload models (Supplemental Figure 8). Thus, the primary difference in sildenafil efficacy between OVX females and males derives from the drug's dependence on estrogen, as the estrogen levels themselves are comparable (25). We further examined this difference in isolated cardiomyocytes in acute settings.…”