Theranostics 2021; 11(19):9397-9414. doi:10.7150/thno.57037 This issue

Research Paper

LncRNA Snhg1-driven self-reinforcing regulatory network promoted cardiac regeneration and repair after myocardial infarction

Mengsha Li1,2,3*, Hao zheng1,2,3*, Yuan Han1,2,3*, Yijin Chen1,2,3, Bing Li1,4, Guojun Chen1,2,3, Xiaoqiang Chen1,2,3, Senlin Huang1,2,3, Xiang He1,2,3, Guoquan Wei1,2,3, Tong Xu1,2,3, Xiaofei Feng1,2,3, Wangjun Liao5, Yulin Liao1,2,3, Yanmei Chen1,2,3✉, Jianping Bin1,2,3✉

1. Department of Cardiology and National Key Lab for Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
2. Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou 510005, China.
3. Guangdong Provincial Key Laboratory of Shock and Microcirculation, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
4. School of Medicine, Guizhou University, Guiyang, Guizhou, 550025, China.
5. Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
*These authors contributed equally to this work.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Li M, zheng H, Han Y, Chen Y, Li B, Chen G, Chen X, Huang S, He X, Wei G, Xu T, Feng X, Liao W, Liao Y, Chen Y, Bin J. LncRNA Snhg1-driven self-reinforcing regulatory network promoted cardiac regeneration and repair after myocardial infarction. Theranostics 2021; 11(19):9397-9414. doi:10.7150/thno.57037. Available from https://www.thno.org/v11p9397.htm

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Abstract

Graphic abstract

Rationale: Most current cardiac regeneration approaches result in very limited cell division and little new cardiomyocyte (CM) mass. Positive feedback loops are vital for cell division, but their role in CM regeneration remains unclear. We aimed to determine whether the lncRNA small nucleolar RNA host gene 1 Snhg1 (Snhg1) could form a positive feedback loop with c-Myc to induce cardiac regeneration.

Methods: Quantitative PCR and in situ hybridization experiments were performed to determine the Snhg1 expression patterns in fetal and myocardial infarction (MI) hearts. Gain- and Loss-of-function assays were conducted to explore the effect of Snhg1 on cardiomyocyte (CM) proliferation and cardiac repair following MI. We further constructed CM-specific Snhg1 knockout mice to confirm the proliferative effect exerted by Snhg1 using CRISPR/Cas9 technology. RNA sequencing and RNA pulldown were performed to explore how Snhg1 mediated cardiac regeneration. Chromatin immunoprecipitation and luciferase reporter assays were used to demonstrate the positive feedback loop between Snhg1 and c-Myc.

Results: Snhg1 expression was increased in human and mouse fetal and myocardial infarction (MI) hearts, particularly in CMs. Overexpression of Snhg1 promoted CM proliferation, angiogenesis, and inhibited CM apoptosis after myocardial infarction, which further improved post-MI cardiac function. Antagonism of Snhg1 in early postnatal mice inhibited CM proliferation and impaired cardiac repair after MI. Mechanistically, Snhg1 directly bound to phosphatase and tensin homolog (PTEN) and induced PTEN degradation, activating the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway to promote CM proliferation. The c-Myc protein, one of downstream targets of PI3K/AKT signaling, functioned as a transcription factor by binding to the promoter regions of Snhg1. Perturbation of the positive feedback between Snhg1 and c-Myc by mutation of the binding sequence significantly affected Snhg1-induced CM proliferation.

Conclusions: Snhg1 effectively elicited CM proliferation and improved cardiac function post-MI by forming a positive feedback loop with c-Myc to sustain PI3K/Akt signaling activation, and thus may be a promising cardiac regeneration strategy in treating heart failure post-MI.

Keywords: Myocardial infarction, Cardiac regeneration, feedback loops, Snhg1, long non-coding RNA