LncRNA4930473A02Rik promotes cardiac hypertrophy by regulating TCF7 via sponging miR-135a in mice

Jing Ren,Hanping Qi,Yawen Xie,Renling Liu,Chao Song,Hongli Sun,Xiang Feng,Lixin Wang,Lina Ba,Meitian Zhang

doi:10.1038/s41420-021-00775-8

Jing Ren, Hanping Qi + Show 8 more

Open Access

https://doi.org/10.1038/s41420-021-00775-8

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Abstract

Cardiac hypertrophy is a common pathological change accompanied by various cardiovascular diseases; however, its underlying mechanisms remain elusive. Mounting evidence indicates that long non-coding RNAs (lncRNAs) are novel transcripts involved in regulating multiple biological processes. However, little is known about their role in regulating cardiac hypertrophy. This study revealed a novel lncRNA4930473A02Rik (abbreviated as lncRNAA02Rik), which showed considerably increased expression in hypertrophic mouse hearts in vivo and angiotensin-II (Ang-II)-induced hypertrophic cardiomyocytes in vitro. Notably, lncRNAA02Rik knockdown partly ameliorated Ang-II induced hypertrophic cardiomyocytes in vitro and hypertrophic mouse heart function in vivo, whereas lncRNAA02Rik overexpression promoted cardiac hypertrophy in vitro. Furthermore, lncRNAA02Rik acted as a competing endogenous RNA by sponging miR-135a, while forced expression of lncRNAA02Rik could repress its activity and expression. Furthermore, forcing miR-135a overexpression exerted a significant protective effect against cardiac hypertrophy by inhibiting the activity of its downstream target TCF7, a critical member of Wnt signaling, and the protective effect could be reversed by AMO-135a. Luciferase assay showed direct interactions among lncRNAA02Rik, miR-135a, and TCF7. Altogether, our study demonstrated that lncRNAA02Rik upregulation could promote cardiac hypertrophy development via modulating miR-135a expression levels and TCF7 activity. Therefore, lncRNAA02Rik inhibition might be considered as a novel potential therapeutic strategy for cardiac hypertrophy.

Highlights

The heart initially develops cardiac hypertrophy under excessive stress as an adaptive response to reduce wall stress and prevent cardiac dysfunction [1, 2]
We reported for the first time that lncRNAA02Rik acted as a regulator of cardiac hypertrophy
We started our research by detecting enhanced lncRNAA02Rik expression in hypertrophic mouse hearts and cardiomyocytes

Summary

INTRODUCTION

The heart initially develops cardiac hypertrophy under excessive stress as an adaptive response to reduce wall stress and prevent cardiac dysfunction [1, 2]. Our previous study indicated that miR-103 negatively affected cardiac hypertrophy via regulating Trpv3 [19]. Numerous studies have indicated that ncRNAs exert a marked effect on cardiac diseases via the Wnt signaling pathway. More research is needed to explore further associations between lncRNAs, miRNAs, and Wnt signaling in cardiac hypertrophy. We identified a new lncRNA, lncRNAA02Rik, which was upregulated in cardiac hypertrophy models in vivo and in vitro and appeared to function as an endogenous RNA to sponge miR-135a. Our study demonstrated effect on lncRNAA02Rik among the three siRNAs. Notably, silencing that lncRNAA02Rik contributed to cardiac hypertrophy via lncRNAA02Rik by siRNA targeting lncRNAA02Rik gene downregusponging miR-135a and activating TCF7, a component of the Wnt signaling pathway.

RESULTS

DISCUSSION AND CONCLUSION

MATERIALS AND METHODS