1. The Smad3-miR-29b/miR-29c axis mediates the protective effect of macrophage migration inhibitory factor against cardiac fibrosis
- Author
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Jie-Ning Zhu, Xian-Hong Fang, Hui Li, Rong Pan, Jian-Fang Luo, Jing Yang, Jin-Dong Xu, Zhen Xiao, Jingnan Liang, Xiao Zou, Ming Zhang, Sheng Wang, Shujing Yuan, Ni Zeng, Zhi-Xin Shan, and Yong-Heng Fu
- Subjects
Male ,0301 basic medicine ,Naringenin ,MMP2 ,Cardiac fibrosis ,Cardiomegaly ,030204 cardiovascular system & hematology ,Matrix (biology) ,Collagen Type I ,Mice ,Transforming Growth Factor beta2 ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Downregulation and upregulation ,otorhinolaryngologic diseases ,medicine ,Animals ,Smad3 Protein ,RNA, Small Interfering ,3' Untranslated Regions ,Macrophage Migration-Inhibitory Factors ,Molecular Biology ,Mice, Knockout ,chemistry.chemical_classification ,Reactive oxygen species ,Myocardium ,Histocompatibility Antigens Class II ,Fibroblasts ,medicine.disease ,Fibrosis ,Up-Regulation ,Antigens, Differentiation, B-Lymphocyte ,Collagen Type I, alpha 1 Chain ,Mice, Inbred C57BL ,MicroRNAs ,030104 developmental biology ,chemistry ,Cancer research ,Matrix Metalloproteinase 2 ,Molecular Medicine ,RNA Interference ,Macrophage migration inhibitory factor ,Transforming growth factor - Abstract
Although macrophage migration inhibitory factor (MIF) is known to have antioxidant property, the role of MIF in cardiac fibrosis has not been well understood. We found that MIF was markedly increased in angiotension II (Ang-II)-infused mouse myocardium. Myocardial function was impaired and cardiac fibrosis was aggravated in Mif-knockout (Mif-KO) mice. Functionally, overexpression of MIF and MIF protein could inhibit the expression of fibrosis-associated collagen (Col) 1a1, COL3A1 and α-SMA, and Smad3 activation in mouse cardiac fibroblasts (CFs). Consistently, MIF deficiency could exacerbate the expression of COL1A1, COL3A1 and α-SMA, and Smad3 activation in Ang-II-treated CFs. Interestingly, microRNA-29b-3p (miR-29b-3p) and microRNA-29c-3p (miR-29c-3p) were down-regulated in the myocardium of Ang-II-infused Mif-KO mice but upregulated in CFs with MIF overexpression or by treatment with MIF protein. MiR-29b-3p and miR-29c-3p could suppress the expression of COL1A1, COL3A1 and α-SMA in CFs through targeting the pro-fibrosis genes of transforming growth factor beta-2 (Tgfb2) and matrix metallopeptidase 2 (Mmp2). We further demonstrated that Mif inhibited reactive oxygen species (ROS) generation and Smad3 activation, and rescued the decrease of miR-29b-3p and miR-29c-3p in Ang-II-treated CFs. Smad3 inhibitors, SIS3 and Naringenin, and Smad3 siRNA could reverse the decrease of miR-29b-3p and miR-29c-3p in Ang-II-treated CFs. Taken together, our data demonstrated that the Smad3-miR-29b/miR-29c axis mediates the inhibitory effect of macrophage migration inhibitory factor on cardiac fibrosis.
- Published
- 2019