MicroRNA-338-3p as a therapeutic target in cardiac fibrosis through FGFR2 suppression.

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.