The Smad3-miR-29b/miR-29c axis mediates the protective effect of macrophage migration inhibitory factor against cardiac fibrosis

Autor: 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, Yong-Heng Fu
Rok vydání: 2019
Předmět:
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
Zdroj: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1865:2441-2450
ISSN: 0925-4439
Popis: 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.
Databáze: OpenAIRE
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