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Estrogen contributes to gender differences in mouse ventricular repolarization.

Tomoaki Saito1, Andrea Ciobotaru, Jean Chrisostome Bopassa

  • 1Department of Anesthesiology, Division of Molecular Medicine, David Geffen School of Medicine at University of California Los Angeles, CA 90095-7115, USA.

Circulation Research
|July 18, 2009
PubMed
Summary
This summary is machine-generated.

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Estrogen significantly impacts cardiac repolarization in mice by reducing key potassium currents (I(to,f) and I(K,slow)). This occurs through downregulation of Kv4.3 and Kv1.5 transcripts, explaining gender-related differences.

Area of Science:

  • Cardiovascular Physiology
  • Molecular Cardiology
  • Endocrinology

Background:

  • Fast-transient outward K(+) (I(to,f)) and ultrarapid delayed rectifier K(+) currents (I(K,slow)) are crucial for cardiac repolarization in mice.
  • Previous studies on gender-related differences in these currents yielded conflicting results, often neglecting the female estral stage.

Purpose of the Study:

  • To investigate gender-related differences in cardiac potassium currents, specifically considering the estral stage in females.
  • To test the hypothesis that estrogen levels influence the densities of K(+) currents involved in ventricular repolarization.

Main Methods:

  • Electrophysiological recordings of total K(+) current (I(K,total)), I(to,f), and I(K,slow) in male and female mice at different estral stages (estrus, diestrus-2).
  • Hormonal manipulation using ovariectomized mice treated with estrogen.

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  • Quantitative analysis of transcript levels for relevant ion channel subunits (Kv4.3, Kv1.5, Kv4.2, KChIP2, Kv2.1).

    • Main Results:

    • Peak I(K,total) densities were significantly higher in males compared to females during estrus, but not diestrus-2.
    • I(to,f) and I(K,slow) densities were lower in females during estrus compared to males and diestrus-2.
    • Estrogen treatment in ovariectomized mice reduced I(K,total), I(to,f), and I(K,slow) densities.
    • Transcript levels of Kv4.3 and Kv1.5 were lower in estrus females and decreased further with estrogen treatment, while other transcripts remained unchanged.
    • Reduced K(+) currents correlated with prolonged action potential duration and corrected QT interval.

    Conclusions:

    • Estrogen downregulates Kv4.3 and Kv1.5 transcripts, representing a key mechanism for gender-related differences in mouse ventricular repolarization.
    • Estral stage and associated estrogen fluctuations are critical factors in determining cardiac repolarization characteristics in female mammals.