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.

The KCNE2 gene encodes a single transmembrane domain protein that modulates a variety of K + channel functions in various tissues. Here we show that cardiac KCNE2 transcript levels are ~10-fold upregulated at the end of pregnancy. This upregulation was mimicked by 17-β estradiol but not by 5α-dihydrotestosterone treatments in ovariectomized mice. To investigate the mechanism of KCNE2 transcriptional regulation by estrogen, we experimentally identified KCNE2 transcription start sites, delineated its gene structure and characterized its promoter region. Estrogen treatment stimulated KCNE2 promoter activity in a dose-dependent manner and ICI 182,780 blocked estrogen stimulation. A direct genomic mechanism was demonstrated by: i) the loss of estrogen responsiveness in the presence of a DNA-binding domain mutant Estrogen Receptor α or mutant KCNE2 ERE and ii) binding of ERα to the KCNE2 ERE. These findings show that a genomic mechanism of estrogen action alters KCNE2 expression, which may have important physiological implications.

showed no structural defects compared to control littermates. Additionally, examination of these hearts by immunofluorescence microscopy revealed normal myofibrillar structure and localization of the transgenic protein to intercalated disks, as normally seen with the endogenous protein. Protein markers for cardiomyopathy were examined by qPCR and revealed no difference between non-transgenic and transgenic animals. Echocardiography and magnetic resonance imaging of the N-RAP transgenic animals revealed no significant structural or functional differences when compared to control littermates at 12 weeks of age. Based on these data, it does not appear that overexpression of N-RAP directly leads to an observable cardiac phenotype. The alternative hypothesis that upregulation of N-RAP in dilated cardiomyopathy is compensatory remains to explored.

DpCa 50 =0.0850.02), while no significant difference was present in sham hearts (DpCa 50 =0.0150.02). These measurements indicate that economy of myofilament contraction is reduced in post-MI remodeled myocardium.