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Published on: March 22, 2017
Integrated bioinformatics analysis and experimental validation reveal circFoxO1 as a regulator of pathological
Huicong Yang1, Jie Lin2, Yongqing Yang1
1Department of Clinical Laboratory, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, Fujian People's Republic of China.
Insights
Circular RNAs (circRNAs) like circFoxO1 are key in pathological cardiac hypertrophy (CHT). This study shows circFoxO1 downregulation exacerbates CHT, suggesting its therapeutic potential for heart conditions.
Area of Science:
- Cardiovascular Biology
- Epigenetics
- Molecular Medicine
Background:
- Pathological cardiac hypertrophy (CHT) is a significant risk factor for heart failure and cardiovascular events.
- Current understanding of CHT molecular mechanisms is limited, hindering effective targeted therapy development.
- Circular RNAs (circRNAs) are emerging as crucial epigenetic regulators in cardiovascular diseases, but their specific roles in CHT are not well-defined.
Purpose of the Study:
- To identify functional circRNAs involved in pathological cardiac hypertrophy (CHT).
- To investigate the role and mechanism of a specific circRNA, circFoxO1, in Angiotensin II-induced CHT.
- To explore the potential of circFoxO1 as a therapeutic target for CHT.
Main Methods:
- Transcriptomic analysis of the GSE148602 dataset combined with machine learning for circRNA prioritization.
- In vitro models using HL-1 cardiomyocytes and in vivo models using C57BL/6 mice subjected to Angiotensin II (AngII) stimulation.
- Gain-of-function experiments for circFoxO1 overexpression and mechanistic studies involving the Wnt/β-catenin signaling pathway.
Main Results:
- Differential expression analysis identified circFoxO1 as a potential regulator in CHT.
- circFoxO1 was significantly downregulated in AngII-induced cardiac hypertrophy models.
- Overexpression of circFoxO1 attenuated AngII-induced cardiomyocyte hypertrophy, reducing hypertrophic markers (ANP, BNP, β-MHC) and influencing the Wnt/β-catenin pathway.
Conclusions:
- circFoxO1 acts as a protective factor against Angiotensin II-induced pathological cardiac hypertrophy.
- The antihypertrophic effect of circFoxO1 involves modulation of the Wnt/β-catenin signaling pathway.
- circFoxO1 represents a potential therapeutic target for mitigating pathological cardiac remodeling.
Abstract:
Pathological Cardiac Hypertrophy (CHT) is a maladaptive response that can lead to heart failure and increase the risk of severe cardiovascular events. However, the molecular mechanisms underlying CHT remain incompletely understood, and effective targeted therapies are still limited in clinical practice. Circular RNAs (circRNAs) emerge as important epigenetic regulators in cardiovascular biology, yet their roles in CHT remain insufficiently characterized. In this study, we combined transcriptomic analysis with in vitro and in vivo experimental models to identify functional circRNAs associated with CHT. Differential expression analysis of the GSE148602 dataset, coupled with machine-learning-assisted prioritization, highlighted circFoxO1 as a potential regulator. Angiotensin II (AngII)-induced hypertrophy models were established in HL-1 cardiomyocytes and C57BL/6 mice, revealing significant downregulation of circFoxO1 under hypertrophic conditions. Gain-of-function experiments demonstrated that circFoxO1 overexpression reduced the expression of classical hypertrophic markers, including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and β-myosin heavy chain (β-MHC), and alleviated AngII-induced cardiomyocyte enlargement. Mechanistic analyses further suggested that circFoxO1 may influence hypertrophic responses through the canonical Wnt/β-catenin signaling pathway, as circFoxO1 overexpression restored Wnt3a and β-catenin expression levels, whereas pharmacological inhibition with FH535 attenuated its antihypertrophic effect. Collectively, these findings indicate that circFoxO1 may modulate AngII-induced CHT and provide additional insight into circRNA-mediated regulatory mechanisms during pathological cardiac remodeling.
