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

Abstract

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.

ASXL3 gene mutations inhibit cell proliferation and promote cell apoptosis in mouse cardiomyocytes by upregulating lncRNA NONMMUT063967.2

“…Moreover, deletion of Fgfr2-IIIb was associated with ventricular abnormalities, including thin myocardial walls, abnormal trabeculae, and muscular VSDs. Huang et al [ 19 ] found that FGFR2 regulates murine cardiac fibroblasts’ activation, proliferation, and migration via miR-338-3p. Furthermore, mutations in p.Ser252Trp and p.Pro253Arg of the FGFR2 gene led to Abbott syndrome associated with the development of CHD [ 20 ].…”

Non-coding RNAs: targets for Chinese herbal medicine in treating myocardial fibrosis

“…Through regulating fibrosis-related factors, miRNA plays various roles in MF. For example, mir-338-3p acts as a therapeutic target in MF through fibroblast growth factor receptor 2 (FGFR2) suppression ( Huang et al, 2022a ). MiR-125b is critical for induction of MF by targeting p53 and Apelin mRNA ( Nagpal et al, 2016 ).…”

Noncoding RNAs: Master Regulator of Fibroblast to Myofibroblast Transition in Fibrosis

“…and ultimately promote the expression of fibrosis-related genes. ncRNA in the MAPK Pathway miR-21 [87], miR-127-3p [88], miR-43 [23], miR-32-5p [89], miR-338-3p [90], miR-155 [91], miR-22 [92], miR-503 [78], lncRNA FENDRR [93], and circEP400 [94] can affect the activation of the MAPK signaling pathway and regulate the differentiation of fibroblasts into myofibroblasts. We found that most of these ncRNAs did not directly target molecules in the MAPK pathway but targeted some proteins regulating the MAPK signaling pathway, such as PDCD4, DUSP1, SPRY1, etc.…”