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Suppression of Pro-fibrotic Signaling Potentiates Factor-mediated Reprogramming of Mouse Embryonic Fibroblasts into Induced Cardiomyocytes
Published on: June 3, 2018
MicroRNA-338-3p as a therapeutic target in cardiac fibrosis through FGFR2 suppression
Cheng Huang1, Rui Wang1, Jianjun Lu2
1Department of Cardiology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangdong Cardiovascular Institute, Guangzhou, China.
Background:
The development of cardiac fibrosis involves the activation of cardiac fibroblasts (CFs) and their differentiation into myofibroblasts, which leads to the disruption of the extracellular matrix network. In the past few years, microRNAs (miRNA) have been described as potential targets for treating cardiac diseases. Although miR-338-3p has been shown to participate in the development of carcinoma, whether it affects cardiac fibrosis is unclear.
Methods:
We examined the expression profiles of microRNAs in left ventricular samples of heart failure mice established by thoracic aortic constriction (TAC). Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to detect the expression of miR-338-3p. CCK-8 assay/Transwell migration assay was used to measure the proliferation rate/migration of CFs. Luciferase reporter gene assay was used to test the binding between miR-338-3p and FGFR2.
Results:
This study demonstrated that miR-338-3p was significantly decreased in thoracic aortic constriction mice. Cardiac miR-338-3p amounts were also reduced in patients with dilated cardiomyopathy (DCM). Interestingly, miR-338-3p overexpression inhibited α-SMA, COL1A1, and COL3A1 expression, as well as cell proliferation and migration in CFs. Bioinformatics analysis and dual-luciferase reporter assays revealed FGFR2 was targeted by miR-338-3p, whose antifibrotic effect could be alleviated by overexpression of FGFR2. Moreover, in DCM cases, serum miR-338-3p levels were markedly elevated in individuals with worse outcomes.
Conclusions:
The present study provides evidence that miR-338-3p suppresses cardiac fibroblast activation, proliferation, and migration by directly targeting FGFR2 in mice. Besides, serum miR-338-3p might constitute a potential prognostic biomarker of dilated cardiomyopathy.
Insights
MicroRNA-338-3p (miR-338-3p) suppresses cardiac fibrosis by targeting FGFR2, inhibiting fibroblast activation and proliferation. Reduced miR-338-3p levels in heart failure and dilated cardiomyopathy suggest its potential as a prognostic biomarker.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Biomarker Discovery
Background:
- Cardiac fibrosis involves cardiac fibroblast (CF) activation and extracellular matrix disruption.
- MicroRNAs (miRNAs) are emerging therapeutic targets for cardiac diseases.
- The role of miR-338-3p in cardiac fibrosis was previously unclear.
Purpose of the Study:
- To investigate the role of miR-338-3p in cardiac fibrosis.
- To identify potential therapeutic targets and biomarkers for cardiac diseases.
Main Methods:
- Examined miRNA expression in heart failure mouse models (thoracic aortic constriction).
- Quantified miR-338-3p expression using qRT-PCR.
- Assessed CF proliferation, migration, and FGFR2 binding via CCK-8, Transwell, and luciferase assays.
Main Results:
- miR-338-3p expression was significantly decreased in mice with thoracic aortic constriction and patients with dilated cardiomyopathy (DCM).
- Overexpression of miR-338-3p inhibited CF activation markers (α-SMA, COL1A1, COL3A1), proliferation, and migration.
- FGFR2 was identified as a direct target of miR-338-3p, mediating its antifibrotic effects.
- Elevated serum miR-338-3p levels correlated with worse outcomes in DCM patients.
Conclusions:
- miR-338-3p suppresses cardiac fibroblast activation, proliferation, and migration by targeting FGFR2.
- Serum miR-338-3p shows potential as a prognostic biomarker for dilated cardiomyopathy.
