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MicroRNA‐146b‐5p promotes atrial fibrosis in atrial fibrillation by repressing TIMP4
- Source :
- Journal of Cellular and Molecular Medicine
- Publication Year :
- 2021
- Publisher :
- John Wiley and Sons Inc., 2021.
-
Abstract
- Alteration of tissue inhibitors of matrix metalloproteinases (TIMP)/matrix metalloproteinases (MMP) associated with collagen upregulation has an important role in sustained atrial fibrillation (AF). The expression of miR‐146b‐5p, whose the targeted gene is TIMPs, is upregulated in atrial cardiomyocytes during AF. This study was to determine whether miR‐146b‐5p could regulate the gene expression of TIMP4 and the contribution of miRNA to atrial fibrosis in AF. Collagen synthesis was observed after miR‐146b‐5p transfection in human induced pluripotent stem cell‐derived atrial cardiomyocytes (hiPSC‐aCMs)‐fibroblast co‐culture cellular model in vitro. Furthermore, a myocardial infarction (MI) mouse model was used to confirm the protective effect of miR‐146b‐5p downregulation on atrial fibrosis. The expression level of miR‐146b‐5p was upregulated, while the expression level of TIMP4 was downregulated in the fibrotic atrium of canine with AF. miR‐146b‐5p transfection in hiPSC‐aCMs‐fibroblast co‐culture cellular model increased collagen synthesis by regulating TIMP4/MMP9 mediated extracellular matrix proteins synthesis. The inhibition of miR‐146b‐5p expression reduced the phenotypes of cardiac fibrosis in the MI mouse model. Fibrotic marker MMP9, TGFB1 and COL1A1 were significantly downregulated, while TIMP4 was significantly upregulated (at both mRNA and protein levels) by miR‐146b‐5p inhibition in cardiomyocytes of MI heart. We concluded that collagen fibres were accumulated in extracellular space on miR‐146b‐5p overexpressed co‐culture cellular model. Moreover, the cardiac fibrosis induced by MI was attenuated in antagomiR‐146 treated mice by increasing the expression of TIMP4, which indicated that the inhibition of miR‐146b‐5p might become an effective therapeutic approach for preventing atrial fibrosis.
- Subjects :
- Male
Heart Diseases
Cardiac fibrosis
Kaplan-Meier Estimate
Matrix metalloproteinase
MMP9
Models, Biological
Extracellular matrix
Electrocardiography
Mice
Dogs
Downregulation and upregulation
Fibrosis
microRNA
Gene expression
Atrial Fibrillation
medicine
Animals
Humans
Myocytes, Cardiac
Cells, Cultured
business.industry
fibrosis
matrix metalloproteinases
Tissue Inhibitor of Metalloproteinases
Cell Biology
Original Articles
Fibroblasts
medicine.disease
Prognosis
Disease Models, Animal
MicroRNAs
Gene Expression Regulation
Cancer research
Molecular Medicine
Original Article
Collagen
Disease Susceptibility
business
metalloproteinases inhibitor 4
Subjects
Details
- Language :
- English
- ISSN :
- 15824934 and 15821838
- Volume :
- 25
- Issue :
- 22
- Database :
- OpenAIRE
- Journal :
- Journal of Cellular and Molecular Medicine
- Accession number :
- edsair.doi.dedup.....eeed9c5c9c4448f32b819b2272acc46e