1. Circular RNA circSMAD4 regulates cardiac fibrosis by targeting miR-671-5p and FGFR2 in cardiac fibroblasts
- Author
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Anna Jeong, Yongwoon Lim, Taewon Kook, Duk-Hwa Kwon, Young Kuk Cho, Juhee Ryu, Yun-Gyeong Lee, Sera Shin, Nakwon Choe, Yong Sook Kim, Hye Jung Cho, Jeong Chul Kim, Yoonjoo Choi, Su-Jin Lee, Hyung-Seok Kim, Hae Jin Kee, Kwang-Il Nam, Youngkeun Ahn, Myung Ho Jeong, Woo Jin Park, Young-Kook Kim, and Hyun Kook
- Subjects
MT: Non-coding RNAs ,circular RNA ,transverse aortic constriction ,cardiac fibrosis ,circSMAD4 ,miR-671-5p ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Heart failure is a leading cause of death and is often accompanied by activation of quiescent cardiac myofibroblasts, which results in cardiac fibrosis. In this study, we aimed to identify novel circular RNAs that regulate cardiac fibrosis. We applied transverse aortic constriction (TAC) for 1, 4, and 8 weeks in mice. RNA sequencing datasets were obtained from cardiac fibroblasts isolated by use of a Langendorff apparatus and then further processed by use of selection criteria such as differential expression and conservation in species. CircSMAD4 was upregulated by TAC in mice or by transforming growth factor (TGF)-β1 in primarily cultured human cardiac fibroblasts. Delivery of si-circSMAD4 attenuated myofibroblast activation and cardiac fibrosis in mice treated with isoproterenol (ISP). si-circSmad4 significantly reduced cardiac fibrosis and remodeling at 8 weeks. Mechanistically, circSMAD4 acted as a sponge against the microRNA miR-671-5p in a sequence-specific manner. miR-671-5p was downregulated during myofibroblast activation and its mimic form attenuated cardiac fibrosis. miR-671-5p mimic destabilized fibroblast growth factor receptor 2 (FGFR2) mRNA in a sequence-specific manner and interfered with the fibrotic action of FGFR2. The circSMAD4-miR-671-5p-FGFR2 pathway is involved in the differentiation of cardiac myofibroblasts and thereby the development of cardiac fibrosis.
- Published
- 2023
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