Cold-inducible RNA-binding protein modulates atrial fibrillation onset by targeting multiple ion channels

Abstract

Background: Atrial fibrillation (AF), the most common sustained arrhythmia, significantly increases cardiovascular and cerebrovascular morbidity and mortality. The pathogenesis and treatment of AF remain a major challenge in the field of cardiology. We previously found that cold-inducible RNA-binding protein (CIRP) regulated ventricular repolarization by posttranscriptionally regulating Kv4.2/4.3 ion channels in rats, but the role of CIRP in AF is not clear.

Objective: The purpose of this study was to confirm that CIRP participates in atrial electrophysiological remodeling and AF occurrence by regulating atrial channels posttranscriptionally.

Methods: Programmed intra-atrial stimulation was used to induce AF in wild-type or transcription activator-like effector nucleases-based CIRP knockout (KO) rats. Atrial optical mapping, patch clamp, Western blotting, RNA immunoprecipitation, and luciferase reporter assays were performed to evaluate the underlying mechanism of atrial electrical remodeling.

Results: First, we observed a shortened atrial effective refractory period and increased susceptibility to AF in CIRP KO rats. Second, atria-specific CIRP delivery through an adeno-associated viral vector serotype 9 prolonged the atrial effective refractory period and attenuated AF development in CIRP KO rats. Third, we observed the shortened action potential duration and enhanced expression of Kv1.5 and Kv4.2/4.3 in KO rats. The transient outward current blocker 4-Aminopyridine and ultrarapid component of the delayed rectifier current blocker Diphenyl phosphine oxide-1 restored the shortened action potential duration in KO atria. Finally, we demonstrated that CIRP suppressed Kv1.5 and Kv4.2/4.3 expression by directly targeting their 3'-untranslated regions.

Conclusion: CIRP plays a protective role in preventing AF onset through the posttranscriptional regulation of Kv1.5 and Kv4.2/4.3.

Keywords: Action potential duration; Atrial effective refractory period; Atrial fibrillation; Cold-inducible RNA binding protein; Ion channels.