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


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.


CONCLUSIONS
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.
Universitätsklinikum, Goethe-Universität, Frankfurt, Germany Universitätsklinikum Erlangen, Erlangen, Germany.
Lars
L
Anneken
Universitätsklinikum, Goethe-Universität, Frankfurt, Germany Universitätsklinikum Mannheim, Mannheim, Germany.
Stefan
S
Baumann
Montreal Heart Institute and Université de Montréal, Montréal, Canada.
Patrick
P
Vigneault
Universitätsklinikum, Goethe-Universität, Frankfurt, Germany.
Peter
P
Biliczki
Institute for Genetics of Heart Diseases, University Hospital Münster, Münster, Germany.
Corinna
C
Friedrich
Montreal Heart Institute and Université de Montréal, Montréal, Canada.
Ling
L
Xiao
Universitätsklinikum, Goethe-Universität, Frankfurt, Germany.
Zenawit
Z
Girmatsion
Cardiovascular Physiology, Goethe-Universität, Frankfurt, Germany.
Ina
I
Takac
Cardiovascular Physiology, Goethe-Universität, Frankfurt, Germany.
Ralf P
RP
Brandes
Universitätsklinikum, Goethe-Universität, Frankfurt, Germany.
Stefan
S
Kissler
Universitätsklinikum, Goethe-Universität, Frankfurt, Germany Kinderwunschpraxis am Goetheplatz, Frankfurt, Germany.
Inka
I
Wiegratz
Institute for Genetics of Heart Diseases, University Hospital Münster, Münster, Germany.
Sven
S
Zumhagen
Institute for Genetics of Heart Diseases, University Hospital Münster, Münster, Germany.
Birgit
B
Stallmeyer
Universitätsklinikum, Goethe-Universität, Frankfurt, Germany.
Stefan H
SH
Hohnloser
Universitätsklinikum, Goethe-Universität, Frankfurt, Germany Praxis für Kardiologie, Bonn, Germany.
Thomas
T
Klingenheben
Institute for Genetics of Heart Diseases, University Hospital Münster, Münster, Germany.
Eric
E
Schulze-Bahr
Montreal Heart Institute and Université de Montréal, Montréal, Canada.
Stanley
S
Nattel
Universitätsklinikum, Goethe-Universität, Frankfurt, Germany Division of Cardiology, St. Josefs-Hospital, Wiesbaden, Germany joachimehrlich@t-online.de.
Joachim R
JR
Ehrlich
D000328:Adult; D016227:Benzoquinones / Q000494:pharmacology; D002996:Clomiphene / Q000627:therapeutic use; D000072237:ERG1 Potassium Channel / Q000235:genetics / Q000378:metabolism*; D004562:Electrocardiography; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000378:metabolism / Q000502:physiology*; D005260:Female; D005300:Fertility Agents, Female / Q000627:therapeutic use; D064368:Healthy Volunteers; D006329:Heart Conduction System / Q000187:drug effects; D006579:Heterozygote; D006801:Humans; D007247:Infertility, Female / Q000235:genetics; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008133:Long QT Syndrome / Q000235:genetics; D008597:Menstrual Cycle; D020125:Mutation, Missense / Q000235:genetics; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular / Q000235:genetics; D011446:Prospective Studies; D021381:Protein Transport / Q000235:genetics
D016227:Benzoquinones; D000072237:ERG1 Potassium Channel; D004791:Enzyme Inhibitors; D005300:Fertility Agents, Female; C000606913:KCNH2 protein, human; D047029:Lactams, Macrocyclic; D002996:Clomiphene; D004958:Estradiol; C001277:geldanamycin
Gender; Hormones; Ion channels; Long-QT syndrome; Repolarization