hsa-miR-4443 inhibits myocardial fibroblast proliferation by targeting THBS1 to regulate TGF-β1/α-SMA/collagen signaling in atrial fibrillation.

Content Provider	Europe PMC
Author	Xiao, Jingwen Zhang, Yan Tang, Yuan Dai, Hengfen OuYang, Yu Li, Chuanchuan Yu, Meiqin
Abstract	Fibrosis caused by the increase in extracellular matrix in cardiac fibroblasts plays an important role in the occurrence and development of atrial fibrillation (AF). The aim of this study was to investigate the role of hsa-miR-4443 in AF, human cardiac fibroblast (HCFB) proliferation, and extracellular matrix remodeling. TaqMan Stem-loop miRNA assay was used to measure hsa-miR-4443 expression in patients with persistent AF (n=123) and healthy controls (n=100). Patients with AF were confirmed to have atrial fibrosis by late gadolinium enhancement. At the cellular level, after hsa-miR-4443 mimic and inhibitor were transfected with HCFBs, proliferation, apoptosis, migration, and invasion were analyzed. Lastly, hsa-miR-4443-targeted gene and transforming growth factor (TGF)-β1/α-SMA/collagen pathway were evaluated by dual-luciferase reporter assay and western blot, respectively. In patients with AF, hsa-miR-4443 decreased significantly and collagen metabolism level increased significantly. Logistic regression analysis showed that low hsa-miR-4443 level was a risk factor of AF (P<0.001). The receiver operating characteristic curve revealed that hsa-miR-4443 was useful for predicting AF (area under the curve: 0.828, sensitivity: 0.71, specificity: 0.78, P<0.001). In HCFBs, hsa-miR-4443 targeted thrombospondin-1 (THBS1) and downregulated TGF-β1/α-SMA/collagen pathway. The inhibition of hsa-miR-4443 expression promoted HCFB proliferation, migration, invasion, myofibroblast differentiation, and collagen production. The significant reduction of hsa-miR-4443 can be used as a biomarker for AF. hsa-miR-4443 protected AF by targeting THBS1 and regulated TGF-β1/α-SMA/collagen pathway to inhibit HCFB proliferation and collagen synthesis.
ISSN	0100879X
Journal	Brazilian Journal of Medical and Biological Research
Volume Number	54
PubMed Central reference number	PMC7931814
Issue Number	4
PubMed reference number	33681892
e-ISSN	1414431X
DOI	10.1590/1414-431X202010692
Language	English
Publisher	Associação Brasileira de Divulgação Científica
Publisher Date	2021-03-03
Access Restriction	Open
Rights License	This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Subject Keyword	Atrial fibrillation hsa-miR-4443 THBS1 TGF-β1/α-SMA/collagen pathway Cardiac fibroblasts Proliferation
Content Type	Text
Resource Type	Article
Subject	Neuroscience Cell Biology Physiology Medicine Biochemistry Biophysics Immunology Pharmacology, Toxicology and Pharmaceutics