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

Abstract

BackgroundCongestive 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 (IK s) in CHF leads to action potential (AP) prolongation, and the IK s is an important contributor to the development of ventricular arrhythmias. However, the molecular mechanisms underlying ventricular arrhythmias are still unknown.Methods and ResultsKcna2 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 IKs 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 IKs, AP prolongation, and ventricular arrhythmias. Kcna2 AS was upregulated ≈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 IKs and the prolongation of APs in vivo and in vitro and reduced ventricular arrhythmias, as detected using electrocardiography.ConclusionsVentricular Kcna2 AS expression increases in rats with CHF and contributes to reduced IK s, 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.

Long Non-Coding RNAs in Atrial Fibrillation: Pluripotent Stem Cell-Derived Cardiomyocytes as a Model System

“…Overexpression of MALAT1 was shown to reduce miR-200c levels, leading to increased expression of high-mobility group box 1 (HMGB1), which decreased expression levels of Kv4.2 and Kv4.3 ion channels, dysregulating cardiac transient outward currents (I to ) [ 90 , 118 ]. LncRNA Kcna2-AS was found to contribute to ventricular arrhythmias [ 91 ]. Kcna2-AS is a negative regulator of Kcna (encoding Kv1.2 potassium channel), which helps control heart rate as well as performing several other physiological functions.…”

Epigenetic Regulation of Alternative mRNA Splicing in Dilated Cardiomyopathy

“…In the literature, lncRNAs were reported to play a role in cardiac development and regeneration, in the pathogenesis of cardiovascular diseases, as well as in the doxorubicin-induced cardiac toxicity, which predisposes people to DCM [48][49][50]. Furthermore, disrupted splicing of lncRNAs were found to cause dysregulation of important cardiac proteins in mice, such as potassium voltage-gated channel proteins encoded by Kcnq1 and Kcna2 [51][52][53]. In addition, a cluster of antisense lncRNAs in the MYH7 locus was noticed to be essential in early development of cardiomyopathy under pressure-overload [54].…”

Investigation of Candidate Genes and Mechanisms Underlying Obesity Associated Type 2 Diabetes Mellitus Using Bioinformatics Analysis and Screening of Small Drug Molecules 

“…The GO and pathway enrichment analysis of DEG are closely related to obesity associated type 2 diabetes mellitus genes and advancement. KCNE5 [45], SHANK3 [46], CASQ2 [47], EDNRA (endothelin receptor type A) [48], EPHB4 [49], ALPK3 [50], WNT11 [51], IRAK2 [52], FBN1 [53], SFRP2 [54], CLCA2 [55], NEXN (nexilin F-actin binding protein) [56], PALLD (palladin, cytoskeletal associated protein) [57], DAB2 [58], NRP2 [59], THBS2 [60], CSF1R [61], KCNA2 [62], CACNA1C [63], F2R [64], UCHL1 [65], CCL18 [66], ITGB1BP2 [67] and FMOD ( bromodulin) [68] were reportedly involved in cardio vascular diseases, but these genes might be key for progression of obesity associated type 2 diabetes mellitus. Hu et al [69], Liu et al [70], Eltokhi et al [71], Cai et al [72], Pfeiffer et al [73], Lin et al [74], Royer-Zemmour et al [75], Pastor et al [76], Goodspeed et al [77], Zhang et al [78], Rogers et al [79], Su et al [80] and Foale et al [81] reported that NRXN1, CRHR1, SHANK2, PSEN2, CKB (creatine kinase B), CD200R1, SRPX2, PTPRZ1, SLC6A1, GABRB2, KCNA1, ASAH1 and LINGO1 were linked with progression of neuropsychiatric disorders, but these genes might be involved in advancement of obesity associated type 2 diabetes mellitus.…”