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Dickkopf 3: a Novel Target Gene of miR-25-3p in Promoting Fibrosis-Related Gene Expression in Myocardial Fibrosis
Ni Zeng1, Yi-Hong Wen1, Rong Pan2
1School of Medicine, South China University of Technology, Guangzhou, 510632, China.
Abstract:
Increasing evidence has shown that microRNAs (miRNAs) participate in cardiac fibrosis. We aimed to elucidate the effect of miRNA miR-25-3p on cardiac fibrosis. MiRNA microarray was used to profile miRNAs in the myocardium of angiotensin-II (Ang-II)-infused mice. Effect of miR-25-3p on expression of fibrosis-related genes, including Col1a1, Col3a1, and Acta2, was investigated both in vitro and in vivo. MiR-25-3p was shown increased in the myocardium of Ang-II-infused mice and patients with heart failure. MiR-25-3p enhanced fibrosis-related gene expression in mouse cardiac fibroblasts (mCFs) and in the myocardium of Ang-II-infused mice. Dickkopf 3 (Dkk3) was identified as a target gene of miR-25-3p, and Dkk3 could ameliorate Smad3 activation and fibrosis-related gene expression via enhancing Smad7 expression in mCFs. Additionally, NF-κB signal was proven to mediate upregulation of miR-25-3p in cardiac fibrosis. Our findings suggest that miR-25-3p enhances cardiac fibrosis by suppressing Dkk3 to activate Smad3 and fibrosis-related gene expression.
Insights
MicroRNA miR-25-3p promotes cardiac fibrosis by targeting Dickkopf 3 (Dkk3). This microRNA (miRNA) increases fibrosis-related gene expression, contributing to heart failure development.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- MicroRNA Research
Background:
- Cardiac fibrosis is a key pathological process in heart failure.
- MicroRNAs (miRNAs) are increasingly recognized for their roles in cardiovascular diseases, including fibrosis.
Purpose of the Study:
- To investigate the specific role of microRNA miR-25-3p in the development of cardiac fibrosis.
- To elucidate the molecular mechanisms by which miR-25-3p influences cardiac fibrosis.
Main Methods:
- MicroRNA microarray analysis to profile miRNA expression in angiotensin-II (Ang-II)-infused mouse hearts.
- In vitro and in vivo experiments to assess the impact of miR-25-3p on fibrosis-related gene expression (Col1a1, Col3a1, Acta2).
- Identification of miR-25-3p target genes and investigation of downstream signaling pathways (Smad3, NF-κB).
Main Results:
- miR-25-3p levels were elevated in the myocardium of Ang-II-infused mice and heart failure patients.
- miR-25-3p significantly enhanced the expression of fibrosis-related genes in mouse cardiac fibroblasts (mCFs) and in vivo.
- Dickkopf 3 (Dkk3) was identified as a direct target of miR-25-3p; Dkk3 ameliorated fibrosis by enhancing Smad7 expression.
- NF-κB signaling pathway was found to mediate the upregulation of miR-25-3p in cardiac fibrosis.
Conclusions:
- miR-25-3p plays a pro-fibrotic role in the heart.
- The mechanism involves the suppression of Dkk3, leading to Smad3 activation and increased expression of fibrosis-related genes.
- NF-κB signaling is implicated in the regulation of miR-25-3p during cardiac fibrosis.
