Dickkopf 3: a Novel Target Gene of miR-25-3p in Promoting Fibrosis-Related Gene Expression in Myocardial Fibrosis

• Published in: Journal of cardiovascular translational research Vol. 14; no. 6; pp. 1051 - 1062
• Main Authors: Zeng, Ni, Wen, Yi-Hong, Pan, Rong, Yang, Jing, Yan, Yu-Min, Zhao, An-Zhi, Zhu, Jie-Ning, Fang, Xian-Hong, Shan, Zhi-Xin
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.12.2021
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Angiotensin II - pharmacology; Animals; Biomedical Engineering and Bioengineering; Biomedicine; Cardiology; Cardiomyopathies - genetics; Female; Fibrosis - genetics; Gene Expression; Human Genetics; Male; Medicine; Medicine & Public Health; Mice; Mice, Inbred C57BL; MicroRNAs - genetics; Original Article; Smad3 Protein - genetics; miR-25-3p; Cardiac fibroblasts; Myocardial fibrosis; Smad3; Dkk3
• ISSN: 1937-5387; 1937-5395
• DOI: 10.1007/s12265-021-10116-w

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. Graphical abstract