LncRNA ZNF593-AS Alleviates Contractile Dysfunction in Dilated Cardiomyopathy

Abstract

Rationale: Previously, we identified the human cardiac long non-coding RNAs (lncRNAs) profile in dilated cardiomyopathy (DCM) patients, among which ZNF593-AS, also named as RP11-96L14.7 and ENST00000448923.2, showed good conservation among species. Objective: We aim to elucidate the mechanism underlying lncRNA in DCM and DCM that lead to heart failure, which might provide new insights into the mechanisms of DCM and possible treatment strategies in the future. Methods and Results: lncRNA expression was measured by real-time PCR and in situ hybridization assays. Coding potential was verified by bioinformatic and biologic assays. Recombinant adeno-associated virus with cardiac specific promoter was used to deliver lncRNA in vivo, while cardiac structure and functions were assessed by echocardiography and catheter. Sarcomere shortening, calcium imaging, gene expression profiling, and pull-down assays were performed to investigate the underlying mechanisms. ZNF593-AS, which mainly localized in the cytoplasm of cardiomyocytes, was robustly decreased in the failing heart of DCM patients, as well as in phenylephrine-treated human cardiomyocytes. Overexpression of mmu-ZNF593-AS significantly improved transverse aortic constriction (TAC)-induced cardiac dysfunction in mice. Moreover, ZNF593-AS overexpression restored the aberrant Ca 2+ handling and contractility of cardiomyocytes from TAC-treated mice. Further, we found that ZNF593-AS acted as a guide RNA scaffold and recruited HNRNPC to ryanodine receptor type 2 (RYR2) mRNA, which in turn facilitated RYR2 mRNA stability, contributed to the improvement of cardiac Ca 2+ handling and contractile function in DCM. Conclusions: Our findings suggested that lncRNA-based therapeutics may protect against DCM.

Expression Profiles and Potential Functions of Long Non-Coding RNAs in the Heart of Mice With Coxsackie B3 Virus-Induced Myocarditis

“…HL-1 cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% fetal bovine serum (FBS) in a humidified atmosphere of 95% air and 5% CO 2 at 37°C, as described previously ( Fan et al., 2021 ). Cells were treated with CVB3 (1 × 10 4 plaque forming unit) and collected 24 h later.…”

LncRNA LOC105378097 inhibits cardiac mitophagy in natural ageing mice

“…Most of these functions are exerted by binding of the lncRNA to proteins, such as transcription factors, chromatin modifiers and other functional proteins. In the last decade, an increasing number of studies indicate the crucial roles of lncRNAs in development and diseases, including ageing and CVDs 9–14 . Our previous studies also revealed that lncRNA could directly bind to target protein, exerting effects on calcium homeostasis and electrical conduction in myocardial infarction and arrhythmia, respectively 13,15–17 .…”

“…In the last decade, an increasing number of studies indicate the crucial roles of lncRNAs in development and diseases, including ageing and CVDs. [9][10][11][12][13][14] Our previous studies also revealed that lncRNA could directly bind to target protein, exerting effects on calcium homeostasis and electrical conduction in myocardial infarction and arrhythmia, respectively. 13,[15][16][17] In cardiovascular senescence, lncRNAs are arising as a new frontier for treatment therapy.…”

Epigenetic Mechanism and Therapeutic Implications of Atrial Fibrillation

“…One study found that ROS levels promotes AF via increased intracellular Ca 2+ release by oxidized RyR2 (6). A recent research found that long non-coding RNA ZNF593-AS facilitated RyR2 mRNA stability (7). The changes in epigenetic state induced by ROS levels could provide the basis for uncovering the pathophysiology and management of AF.…”