Kcne2 Expression is Regulated both by Estrogen and Cardiac Stress in the Adult Male Mouse Heart

Abstract

KCNE2 is a single transmembrane modulatory β subunit that can modulate a variety of K+ channel pore-forming α subunits in heterologous systems; recently we have shown KCNE2 to be an estrogen-responsive gene. KCNE2 is linked to LQTs and fatal arrhythmia. Pathological heart hypertrophy is associated with abnormal electrical activity leading to a considerable propensity to arrhythmias. We hypothesized KCNE2 expression might be modulated by pathological heart hypertrophy and by estrogen. The trans-aortic constriction (TAC) procedure was used to induce pressure overload and eventually heart failure (TAC-HF) in male mice. Once the ejection fraction reached ∼30%, the mice were treated with estrogen for 10 days. Real-time PCR showed that transcript levels of KCNE2 were similar between TAC-HF and control (CTRL), while strikingly upregulated ∼3 fold by estrogen treatment. To gain insight into the KCNE2 cell biology in heart failure and after treatment with estrogen, isolated cardiomyocytes were labeled with anti-KCNE2 antibody. In healthy hearts, KCNE2 was distributed both at the surface membrane as well as in the T-tubules, while in failing hearts KCNE2 completely disappeared from the T-tubules but its surface plasma membrane labeling increased. The disappearance of KCNE2 from the T-tubules in TAC-HF was not due to the disruption of their structure, since their integrity was maintained as evident by a similar α-actinin labeling in control and TAC-HF. E2 treatment of TAC-HF significantly increased overall KCNE2 labeling; KCNE2 was distributed both at the surface membrane as well as in the T-tubules. We speculate higher KCNE2 transcript levels, as well as reappearance of KCNE2 in the T-tubules by estrogen treatment of TAC-HF, would increase the association of KCNE2 with Kv4.3 and/or Kv4.2, therefore potentiating Ito,f currents thus resulting in a better cardiac repolarization.