miR-448 regulates potassium voltage-gated channel subfamily A member 4 (KCNA4) in ischemia and heart failure

Background: MicroRNA miR-448 mediates some of the effects of ischemia on arrhythmic risk. Potassium voltage-gated channel subfamily A member 4 (KCNA4) encodes a K_v1.4 current that opens in response to membrane depolarization and is essential for regulating the action potential duration in heart. KCNA4 has a miR-448 binding site.

Objective: We investigated whether miR-448 was involved in the regulation of KCNA4 messenger RNA expression in ischemia.

Methods: Quantitative real-time reverse-transcriptase polymerase chain reaction was used to investigate the expression of KCNA4 and miR-448. Pull-down assays were used to examine the interaction between miR-448 and KCNA4. miR-448 decoy and binding site mutation were used to examine the specificity of the effect for KCNA4.

Results: The expression of KCNA4 is diminished in ischemia and human heart failure tissues with ventricular tachycardia. Previously, we have shown that miR-448 is upregulated in ischemia and inhibition can prevent arrhythmic risk after myocardial infarction. The 3'-untranslated region of KCNA4 has a conserved miR-448 binding site. miR-448 bound to this site directly and reduced KCNA4 expression and the transient outward potassium current. Inhibition of miR-448 restored KCNA4.

Conclusion: These findings showed a link between K_v1.4 downregulation and miR-448-mediated upregulation in ischemia, suggesting a new mechanism for the antiarrhythmic effect of miR-448 inhibition.