Multiscale drug screening for cardiac fibrosis identifies MD2 as a therapeutic target
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE274781 | GEO | 2024/10/15
REPOSITORIES: GEO
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Project description:Multiscale drug screening for cardiac fibrosis identifies MD2 as a therapeutic target
| PRJNA1148035 | ENA
Project description:Multiscale Drug Screening for Cardiac Fibrosis Identifies MD2 as a Therapeutic Target
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Project description:Multiscale drug screening for cardiac fibrosis identifies MD2 as a therapeutic target
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Project description:BackgroundThe 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.MethodsWe 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.ResultsThis 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.ConclusionsThe 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.
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Project description:Cardiac fibrosis is the final common pathology in heart disease. Here we establish an integrated imaging-genomic discovery platform using primary human heart fibroblasts to identify new drug targets for cardiac fibrosis. Genome wide analyses identify IL11, a secreted cytokine amenable to therapeutic inhibition, as the leading pro-fibrotic candidate. We demonstrate an autocrine loop of IL11 activity that is critical for fibrosis and acts as a nexus of signalling convergence for multiple pro-fibrotic stimuli. IL11 signals in cis and trans via the ERK cascade to activate a programme of fibrosis primarily at the level of protein translation. Injection of IL11 to mice causes fibrosis of the heart, kidney, lung, skin and liver whereas genetic ablation of the IL11 receptor prevented fibrosis across tissues. These data define a new non-canonical fibrogenic pathway and prioritise IL11 as a novel therapeutic target for fibrosis of the heart and other organs
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