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Updated: Dec 9, 2025
Suppression of Pro-fibrotic Signaling Potentiates Factor-mediated Reprogramming of Mouse Embryonic Fibroblasts into Induced Cardiomyocytes
Published on: June 3, 2018
CircHIPK3 regulates cardiac fibroblast proliferation, migration and phenotypic switching through the
Weiwei Liu1, Yan Wang1, Zhimei Qiu1
1Department of Cardiology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.
Insights
Circular RNA HIPK3 (circHIPK3) promotes cardiac fibrosis under hypoxia by sponging miR-152-3p and upregulating TGF-β2. Modulating circHIPK3 may offer a therapeutic target for hypoxia-induced cardiac remodeling.
Area of Science:
- Cardiovascular Biology
- Molecular Biology
- Epigenetics
Background:
- Pathological cardiac fibrosis is linked to tissue hypoxia.
- Circular RNAs (circRNAs) are key regulators in cardiovascular diseases.
- CircHIPK3 is implicated in cardiac fibrosis, but its hypoxia-related mechanisms are unknown.
Purpose of the Study:
- To determine circHIPK3 expression in cardiac fibroblasts (CFs) under hypoxia.
- To investigate the functional role of circHIPK3 in CFs within a hypoxic environment.
- To elucidate the molecular mechanisms underlying circHIPK3-mediated cardiac fibrosis.
Main Methods:
- Quantitative real-time PCR (qRT-PCR) for circHIPK3 expression analysis.
- Cell proliferation (EdU), migration (wound scratch), and cell cycle assays.
- Immunofluorescence, Western blot, bioinformatics, dual luciferase, and RNA FISH assays to identify molecular interactions.
Main Results:
- CircHIPK3 expression significantly increased in CFs under hypoxia.
- Overexpression of circHIPK3 promoted CF proliferation, migration, and phenotypic changes; silencing had the opposite effect.
- CircHIPK3 functions as a miR-152-3p sponge, with miR-152-3p targeting TGF-β2.
Conclusions:
- CircHIPK3 promotes hypoxia-induced cardiac fibrosis by regulating the miR-152-3p/TGF-β2 axis.
- CircHIPK3 influences CF proliferation, migration, and transformation to myofibroblasts.
- Targeting circHIPK3 presents a potential therapeutic strategy for cardiac fibrosis.
Background:
The occurrence of pathological cardiac fibrosis is attributed to tissue hypoxia. Circular RNAs play significant regulatory roles in multiple cardiovascular diseases and are involved in the regulation of physiological and pathophysiological processes. CircHIPK3 has been identified as the one of the most crucial regulators in cardiac fibrosis. However, the mechanisms by which circHIPK3 regulates cardiac fibrosis under hypoxia remain unclear. Our study aimed to determine circHIPK3 expression in cardiac fibroblasts (CFs) and investigate the functions of circHIPK3 in hypoxia environment.
Methods:
The expression level of circHIPK3 in CFs under hypoxia (1% O2) was analyzed by qRT-PCR. The role of circHIPK3 on the proliferation and migration of CFs were determined by EdU, cell wound scratch assay and cell cycle. The expression of proteins associated with phenotypic transformation in CFs in vitro was examined by immunofluorescence assay and western blot. Bioinformatics analysis, dual luciferase activity assay and RNA fluorescent in situ hybridization assay revealed that miR-152-3p was identified as a target of circHIPK3 and that TGF-β2 was targeted by miR-152-3p.
Results:
CircHIPK3 expression was significantly upregulated in CFs in a hypoxic environment. In vitro, overexpressing circHIPK3 obviously promoted CF proliferation, migration and phenotypic changes under hypoxia, but those processes were suppressed by circHIPK3 silencing. CircHIPK3 acted as an endogenous miR-152-3p sponge and miR-152-3p aggravated circHIPK3 silencing induced inhibition of CF proliferation, migration, phenotypic transformation and TGF-β2 expression in vitro. In summary, circHIPK3 plays a pivotal role in the development of cardiac fibrosis by targeting the miR-152-3p/TGF-β2 axis.
Conclusions:
These findings demonstrated that circHIPK3 acted as a miR-152-3p sponge to regulate CF proliferation, migration and phenotypic transformation through TGF-β2, revealing that modulation of circHIPK3 expression may represent a potential target to promote the transition of hypoxia-induced CFs to myofibroblasts.
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