Feedback Remodeling of Cardiac Potassium Current Expression: A Novel Potential Mechanism for Control of Repolarization Reserve

Background— Inhibition of individual K+ currents causes functionally based compensatory increases in other K+ currents that minimize changes in action potential duration, a phenomenon known as repolarization reserve. The possibility that sustained K+ channel inhibition may induce remodeling of ion current expression has not been tested. Accordingly, we assessed the effects of sustained inhibition of one K+ current on various other cardiac ionic currents. Methods and Results— Adult canine left ventricular cardiomyocytes were incubated in primary culture and paced at a physiological rate (1 Hz) for 24 hours in the presence or absence of the highly selective rapid delayed-rectifier K+ current (IKr) blocker dofetilide (5 nmol/L). Sustained dofetilide exposure led to shortened action potential duration and increased repolarization reserve (manifested as a reduced action potential duration–prolonging response to IKr blockade). These repolarization changes were accompanied by increased slow delayed-rectifier (IKs) density, whereas IKr, transient-outward (Ito), inward-rectifier (IK1), L-type Ca2+ (ICaL), and late Na+ current remained unchanged. The mRNA expression corresponding to KvLQT1 and minK (real-time polymerase chain reaction) was unchanged, but their protein expression (Western blot) was increased, suggesting posttranscriptional regulation. To analyze possible mechanisms, we quantified the muscle-specific microRNA subtypes miR-133a and miR-133b, which can posttranscriptionally regulate and repress KvLQT1 protein expression without affecting mRNA expression. The expression levels of miR-133a and miR-133b were significantly decreased in cells cultured in dofetilide compared with control, possibly accounting for KvLQT1 protein upregulation. Conclusions— Sustained reductions in IKr may lead to compensatory upregulation of IKs through posttranscriptional upregulation of underlying subunits, likely mediated (at least partly) by microRNA changes. These results suggest that feedback control of ion channel expression may influence repolarization reserve.