Estradiol regulates human QT-interval: Acceleration of cardiac repolarization by enhanced KCNH2 membrane trafficking

Lars Anneken, Stefan Baumann, Patrick Vigneault, Peter Biliczki, Corinna Friedrich, Ling Xiao, Zenawit Girmatsion, Ina Takac, Ralf P. Brandes, Stefan Kissler, Inka Wiegratz, Sven Zumhagen, Birgit Stallmeyer, Stefan H. Hohnloser, Thomas Klingenheben, Eric Schulze-Bahr, Stanley Nattel, Joachim R. Ehrlich

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25 Citations (Scopus)

Abstract

Background Modulation of cardiac repolarization by sexual hormones is controversial and hormonal effects on ion channels remain largely unknown. In the present translational study, we therefore assessed the relationship between QTc duration and gonadal hormones and studied underlying mechanisms. Methods and results We measured hormone levels and QTc intervals in women during clomiphene stimulation for infertility and women before, during, and after pregnancy. Three heterozygous LQT-2 patients (KCNH2-p.Arg752Pro missense mutation) and two unaffected family members additionally were studied during their menstrual cycles. A comprehensive cellular and molecular analysis was done to identify the mechanisms of hormonal QT-interval regulation. High estradiol levels, but neither progesterone nor estradiol/progesterone ratio, inversely correlated with QTc. Consistent with clinical data, in vitro estradiol stimulation (60 pmol/L, 48 h) enhanced IKCNH2. This increase was mediated by estradiol receptor-α-dependent promotion of KCNH2-channel trafficking to the cell membrane. To study the underlying mechanism, we focused on heat-shock proteins. The heat-shock protein-90 (Hsp90) inhibitor geldanamycin abolished estradiol-induced increase in IKCNH2. Geldanamycin had no effect on KCNH2 transcription or translation; nor did it affect expression of estradiol receptors and chaperones. Estradiol enhanced the physical interaction of KCNH2-channel subunits with heat-shock proteins and augmented ion-channel trafficking to the membrane. Conclusion Elevated estradiol levels were associated with shorter QTc intervals in healthy women and female LQT-2 patients. Estradiol acts on KCNH2 channels via enhanced estradiol-receptor-α-mediated Hsp90 interaction, augments membrane trafficking and thereby increases repolarizing current. These results provide mechanistic insights into hormonal control of human ventricular repolarization and open novel therapeutic avenues.

Original languageEnglish
Pages (from-to)640-650
Number of pages11
JournalEuropean heart journal
Volume37
Issue number7
DOIs
Publication statusPublished - Feb 14 2016

Keywords

  • Gender
  • Hormones
  • Ion channels
  • Long-QT syndrome
  • Repolarization

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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    Anneken, L., Baumann, S., Vigneault, P., Biliczki, P., Friedrich, C., Xiao, L., Girmatsion, Z., Takac, I., Brandes, R. P., Kissler, S., Wiegratz, I., Zumhagen, S., Stallmeyer, B., Hohnloser, S. H., Klingenheben, T., Schulze-Bahr, E., Nattel, S., & Ehrlich, J. R. (2016). Estradiol regulates human QT-interval: Acceleration of cardiac repolarization by enhanced KCNH2 membrane trafficking. European heart journal, 37(7), 640-650. https://doi.org/10.1093/eurheartj/ehv371