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Published on: June 3, 2018
Loss of circIGF1R Suppresses Cardiomyocytes Proliferation by Sponging miR-362-5p
Jun-Hui Zeng1, Hong-Ji Li1, Kun Liu1
1Key Laboratory of Regenerative Medicine of Ministry of Education, Department of Developmental & Regenerative Biology, Jinan University, Guangzhou, China.
Insights
Circular RNAs (circRNAs) regulate cardiomyocyte proliferation. Circ-insulin-like growth factor 1 receptor (circIGF1R) promotes proliferation by sponging miR-362-5p, increasing PHF3 expression, crucial for heart regeneration.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Epigenetics
Background:
- Circular RNAs (circRNAs) are increasingly recognized for their roles in cardiovascular diseases.
- The specific function of circ-insulin-like growth factor 1 receptor (circIGF1R) in cardiomyocyte proliferation is not well understood.
Purpose of the Study:
- To investigate the role of circIGF1R in cardiomyocyte proliferation.
- To elucidate the molecular mechanism by which circIGF1R influences cardiomyocyte growth.
Main Methods:
- Expression analysis of circIGF1R, miR-362-5p, and PHF3 in neonatal and adult mouse hearts, and in injured hearts.
- Functional assays involving circIGF1R knockdown and miR-362-5p mimics/inhibition in primary cardiomyocytes.
- Luciferase reporter assays to confirm the interaction between circIGF1R and miR-362-5p.
- Quantitative real-time PCR (qPCR) for gene expression validation.
Main Results:
- circIGF1R expression was lower in adult hearts and increased in injured neonatal hearts.
- circIGF1R knockdown inhibited cardiomyocyte proliferation, while its overexpression promoted it.
- circIGF1R directly interacted with miR-362-5p, acting as a sponge.
- miR-362-5p suppressed cardiomyocyte proliferation and targeted PHF3.
- PHF3 expression was decreased in adult hearts and increased in injured neonatal hearts.
- Knockdown of PHF3 inhibited cardiomyocyte proliferation.
Conclusions:
- circIGF1R promotes cardiomyocyte proliferation by sponging miR-362-5p, leading to increased PHF3 expression.
- This circIGF1R/miR-362-5p/PHF3 axis is a novel regulatory pathway for cardiomyocyte proliferation and heart regeneration.
Abstract:
Circular RNAs (circRNAs) are generally formed by the back-splicing of precursor mRNA. Increasing evidence implicates the important role of circRNAs in cardiovascular diseases. However, the role of circ-insulin-like growth factor 1 receptor (circIGF1R) in cardiomyocyte (CM) proliferation remains unclear. Here, we investigated the potential role of the circIGF1R in the proliferation of CMs. We found that circIGF1R expression in heart tissues and primary CMs from adult mice was significantly lower than that in neonatal mice at postnatal 1 day (p1). Increased circIGF1R expression was detected in the injured neonatal heart at 0.5 and 1 days post-resection. circIGF1R knockdown significantly decreased the proliferation of primary CMs. Combined prediction software, luciferase reporter gene analysis, and quantitative real time-PCR (qPCR) revealed that circIGF1R interacted with miR-362-5p. A significant increase in miR-362-5p expression was detected in the adult heart compared with that in the neonatal heart. Further, heart injury significantly decreased the expression of miR-362-5p in neonatal mice. Treatment with miR-362-5p mimics significantly suppressed the proliferation of primary CMs, whereas knockdown of miR-362-5p promoted the CMs proliferation. Meanwhile, miR-362-5p silencing can rescue the proliferation inhibition of CMs induced by circIGF1R knockdown. Target prediction and qPCR validation revealed that miR-362-5p significantly inhibited the expression of Phf3 in primary CMs. In addition, decreased Phf3 expression was detected in adult hearts compared with neonatal hearts. Consistently, increased Phf3 expression was detected in injured neonatal hearts compared with that in sham hearts. Knockdown of Phf3 markedly repressed CMs proliferation. Taken together, these findings suggest that circIGF1R might contribute to cardiomyocyte proliferation by promoting Pfh3 expression by sponging miR-362-5p and provide an important experimental basis for the regulation of heart regeneration.
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