Circ-sh3rf3/GATA-4/miR-29a regulatory axis in fibroblast–myofibroblast differentiation and myocardial fibrosis

• Published in: Cellular and molecular life sciences : CMLS Vol. 80; no. 2; p. 50
• Main Authors: Ma, Cai-Xia, Wei, Zhi-Ru, Sun, Tong, Yang, Ming-Hui, Sun, Yu-Qie, Kai, Kun-Lun, Shi, Jia-Chen, Zhou, Meng-Jiao, Wang, Zi-Wei, Chen, Jing, Li, Wei, Wang, Tian-Qi, Zhang, Shan-Feng, Xue, Lixiang, Zhang, Min, Yin, Qianqian, Zang, Ming-Xi
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01-02-2023; Springer Nature B.V
• Subjects: Animals; Biochemistry; Biomedical and Life Sciences; Biomedicine; Cardiomyocytes; Cardiomyopathies - genetics; Cardiomyopathies - metabolism; Cardiomyopathies - pathology; Cell Biology; Cell Differentiation - genetics; Cell Differentiation - physiology; Circular RNA; Differentiation; Fibroblasts; Fibroblasts - metabolism; Fibrosis; Fibrosis - genetics; Fibrosis - metabolism; Heart; Hypertrophy; Isoproterenol; Life Sciences; MicroRNAs - genetics; MicroRNAs - metabolism; Myocytes, Cardiac - metabolism; Myofibroblasts - metabolism; Original; Original Article; Rats; RNA, Circular - genetics; RNA, Circular - metabolism; Therapeutic targets; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; microRNAs; Circular RNA; Fibroblast–myofibroblast differentiation; Myocardial fibrosis
• ISSN: 1420-682X; 1420-9071
• DOI: 10.1007/s00018-023-04699-7

The transdifferentiation from cardiac fibroblasts to myofibroblasts is an important event in the initiation of cardiac fibrosis. However, the underlying mechanism is not fully understood. Circ-sh3rf3 (circular RNA SH3 domain containing Ring Finger 3) is a novel circular RNA which was induced in hypertrophied ventricles by isoproterenol hydrochloride, and our work has established that it is a potential regulator in cardiac hypertrophy, but whether circ-sh3rf3 plays a role in cardiac fibrosis remains unclear, especially in the conversion of cardiac fibroblasts into myofibroblasts. Here, we found that circ-sh3rf3 was down-regulated in isoproterenol-treated rat cardiac fibroblasts and cardiomyocytes as well as during fibroblast differentiation into myofibroblasts. We further confirmed that circ-sh3rf3 could interact with GATA-4 proteins and reduce the expression of GATA-4, which in turn abolishes GATA-4 repression of miR-29a expression and thus up-regulates miR-29a expression, thereby inhibiting fibroblast–myofibroblast differentiation and myocardial fibrosis. Our work has established a novel Circ-sh3rf3/GATA-4/miR-29a regulatory cascade in fibroblast–myofibroblast differentiation and myocardial fibrosis, which provides a new therapeutic target for myocardial fibrosis.