Cardiac Kv4.3 and KCNE2 Are Differentially Regulated by E2 and Have Different Sensitivities to Local Heart E2 Concentrations

Abstract

Recently we reported that the KCNE2 gene is an estrogen-responsive gene and its transcripts are upregulated 6 fold by estrogen (E2) in ovariectomized (ovx) mice1. We have also shown that cardiac Kv4.3 transcripts were downregulated ∼2 fold by E22. As the effect of E2 treatment was more powerful on KCNE2 upregulation than Kv4.3 downregulation, we hypothesized that cardiac Kv4.3 and KCNE2 have different sensitivities to heart E2 concentrations [E2]. We measured heart [E2] together with KCNE2 and Kv4.3 transcript levels in 4 estrogenic conditions: i) E2-depleted (anastrozole treated mice, [E2]=4.2±0.4 pg/ml n=4; ii) low E2 (ovx sham, [E2]=16±1.4 pg/ml n=3 and diestrus [E2]=20.2±1.5 n=4), iii) intermediate E2 (male [E2]=35±3 pg/ml, n=6) and iv) high E2 (ovx mice treated with E2, [E2]=62.7±2.9 pg/ml, n=3). Kv4.3 transcript levels were not affected by heart [E2] lower than 35 pg/ml whereas KCNE2 transcript levels were very sensitive to this range of heart [E2], reaching a ∼10 fold increase from low to intermediate heart [E2], saturating at 35 pg/ml. The fact that Kv4.3 levels were unaffected by anastrozole treatment, whereas KCNE2 levels were dramatically reduced by ∼8 fold by anastrozole, further supports the finding that KCNE2 upregulation can take place at very low E2 levels. The downregulation of Kv4.3 transcripts were only evident at high estrogenic conditions, whereas KCNE2 remains at its maximum. As Kv4.3 is one of the molecular correlate of Ito,f and it has also been shown that KCNE2 can potentiate Kv4.3 currents in the expression system, we speculate that the relative expression of KCNE2 and Kv4.3 as defined by heart [E2] will determine Ito,f amplitude.1. Kundu et al., Mol Cell Endocrinol 2008;292:50-62.2. Eghbali et al., Circ Res 2005;96:1208-16.