Long Noncoding RNA Kcna2 Antisense RNA Contributes to Ventricular Arrhythmias via Silencing Kcna2 in Rats With Congestive Heart Failure

Background-Congestive heart failure (CHF) is a common cardiovascular disease that is often accompanied by ventricular arrhythmias. The decrease of the slow component of the delayed rectifier potassium current (I-Ks) in CHF leads to action potential (AP) prolongation, and the I-Ks is an important contributor to the development of ventricular arrhythmias. However, the molecular mechanisms underlying ventricular arrhythmias are still unknown. Methods and Results-Kcna2 and Kcna2 antisense RNA (Kcna2 AS) transcript expression was measured in rat cardiac tissues using quantitative real-time reverse transcription-polymerase chain reaction and Western blotting. There was a 43% reduction in Kcna2 mRNA in the left ventricular myocardium of rats with CHF. Kcna2 knockdown in the heart decreased the I-Ks and prolonged APs in cardiomyocytes, consistent with the changes observed in heart failure. Conversely, Kcna2 overexpression in the heart significantly attenuated the CHF-induced decreases in the I-Ks, AP prolongation, and ventricular arrhythmias. Kcna2 AS was upregulated approximate to 1.7-fold in rats with CHF and with phenylephrine-induced cardiomyocyte hypertrophy. Kcna2 AS inhibition increased the CHF-induced downregulation of Kcna2. Consequently, Kcna2 AS mitigated the decrease in the I-Ks and the prolongation of APs in vivo and in vitro and reduced ventricular arrhythmias, as detected using electrocardiography. Conclusions-Ventricular Kcna2 AS expression increases in rats with CHF and contributes to reduced I-Ks, prolonged APs, and the occurrence of ventricular arrhythmias by silencing Kcna2. Thus, Kcna2 AS may be a new target for the prevention and treatment of ventricular arrhythmias in patients with CHF.