Kcne4 deletion sex-specifically predisposes to cardiac arrhythmia via testosterone-dependent impairment of RISK/SAFE pathway induction in aged mice

Scientific Reports
Zhaoyang HuGeoffrey W Abbott

Abstract

Sudden cardiac death (SCD) is associated with both electrical and ischemic substrates, and is a major cause of ischemic heart disease mortality worldwide. Male sex predisposes to SCD but the underlying mechanisms are incompletely understood. KCNE4, a cardiac arrhythmia-associated potassium channel β-subunit, is upregulated by 5α-dihydrotestosterone (DHT). Thus, ventricular Kcne4 expression is low in young adult female mice, but high in males and postmenopausal (12+ months) females. Despite causing a sex-independent electrical substrate at 13 months of age (22% QT prolongation in both males and females; P < 0.01), Kcne4 deletion preferentially predisposed aged male mice to ischemia/reperfusion (IR)-provoked ventricular tachyarrhythmias. Interestingly, Kcne4 deletion caused baseline induction of cardioprotective RISK and SAFE pathways in 13-m-old female, but not male, mice. IR-invoked RISK/SAFE induction was also deficient in male but not female Kcne4-/- mice. Pharmacological inhibition of RISK/SAFE pathways in Kcne4-/- females eliminated sex-specific differences in IR-invoked tachyarrhythmia predisposition. Furthermore, castration of Kcne4-/- males eliminated sex-specific differences in both baseline and post-IR RISK/SAFE pathwa...Continue Reading

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Citations

Oct 6, 2018·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Jens-Peter DavidGeoffrey W Abbott
Feb 14, 2019·American Journal of Physiology. Regulatory, Integrative and Comparative Physiology·Zhaoyang HuGeoffrey W Abbott

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Software Mentioned

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ImageJ
LabChart7

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