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MicroRNA-133 suppresses ZFHX3-dependent atrial remodelling and arrhythmia
Wan-Li Cheng1, Yu-Hsun Kao1,2, Tze-Fan Chao3
1Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Aim:
Atrial fibrillation (AF) is an important cause of morbidity and mortality in the modern world. Loss-of-function mutation in the zinc finger homeobox 3 gene (ZFHX3) is associated with increased risk of AF. MicroRNAs (miRNAs) participate in arrhythmogenesis, and thus miRNA modulators may be applicable as therapeutic modalities for AF. However, the altered miRNA profiles after ZFHX3 knockdown (KD) remain unclear. This study aimed to analyse the changes of miRNA expression in loss-of-function of ZFHX3 and the effect of miRNA modulation on atrial arrhythmias in this model.
Methods:
We performed small RNA deep sequencing on ZFHX3-KD and control HL-1 mouse atrial myocytes. The effect of miRNAs on ZFHX3-dependent atrial arrhythmia was evaluated through in vitro and in vivo assays in mice.
Results:
Among the differentially expressed miRNAs, 11 were down-regulated and 6 were up-regulated after ZFHX3 KD. Quantitative real-time PCR analysis confirmed that after ZFHX3 KD, miR-133a and miR-133b were significantly down-regulated, whereas miR-184 was the most significantly up-regulated. DIANA-miRPath analysis suggested that miR-133a/b down-regulation increases the targeted signalling of miR-133 (ie, adrenergic, Wnt/calcium and fibroblast growth factor receptor 1 signalling), which could contribute to pathological remodelling of cardiomyocytes. These results were confirmed through Western blotting. After transfection of miR-133a/b mimics in ZFHX3-KD cells, miR-133a/b levels increased, accompanied by the inhibition of their target signalling. Treatment with miR-133a/b mimics diminished ZFHX3 KD-induced atrial ectopy in mice.
Conclusion:
ZFHX3-KD promotes distinct miRNA expressional changes in atrial myocytes. MiR-133a/b mimics may reverse signalling of ZFHX3 KD-mediated cardiac remodelling and atrial arrhythmia.
Insights
Loss-of-function mutations in the zinc finger homeobox 3 gene (ZFHX3) increase atrial fibrillation risk. Restoring miR-133a/b levels may reverse ZFHX3-related cardiac remodeling and arrhythmias.
Area of Science:
- Cardiology
- Molecular Biology
- Genetics
Background:
- Atrial fibrillation (AF) is a significant global health concern linked to increased morbidity and mortality.
- Loss-of-function mutations in the zinc finger homeobox 3 gene (ZFHX3) are identified as a risk factor for AF.
- MicroRNAs (miRNAs) play a role in arrhythmogenesis, suggesting their potential as therapeutic targets for AF.
Purpose of the Study:
- To investigate the altered miRNA expression profiles following ZFHX3 knockdown (KD) in atrial myocytes.
- To explore the therapeutic potential of miRNA modulation in a ZFHX3-dependent atrial arrhythmia model.
Main Methods:
- Small RNA deep sequencing was performed on ZFHX3-KD and control HL-1 mouse atrial myocytes.
- In vitro and in vivo assays in mice were utilized to evaluate the effect of miRNAs on ZFHX3-dependent atrial arrhythmia.
- Quantitative real-time PCR and Western blotting were employed for validation.
Main Results:
- ZFHX3 KD led to differential expression of miRNAs, with miR-133a/b significantly downregulated and miR-184 upregulated.
- Downregulation of miR-133a/b was associated with increased signaling pathways implicated in pathological cardiomyocyte remodeling.
- Transfection with miR-133a/b mimics in ZFHX3-KD cells inhibited target signaling and reduced atrial ectopy in mice.
Conclusions:
- ZFHX3 knockdown induces specific miRNA expression changes in atrial myocytes.
- Modulation of miR-133a/b using mimics shows potential to reverse ZFHX3 KD-mediated cardiac remodeling and atrial arrhythmia.
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