Crucial Role of miR-433 in Regulating Cardiac Fibrosis.
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ABSTRACT:
SUBMITTER: Tao L
PROVIDER: S-EPMC5039681 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Cardiac fibrosis is the pathological consequence of fibroblast proliferation and fibroblast-to-myofibroblast transition. As a new class of endogenous non-coding RNAs, circular RNAs (circRNAs) have been identified in many cardiovascular diseases including fibrosis, generally acting as microRNA (miRNA) sponges. Here, we report that the expression of circRNA-circNFIB was decreased in mice post-myocardial infarction heart samples, as well as in primary adult cardiac fibroblasts treated with TGF-β. Forced expression of circNFIB decreased cell proliferation in both NIH/3T3 cells and primary adult fibroblasts as evidenced by EdU incorporation. Conversely, inhibition of circNFIB promoted adult fibroblast proliferation. Furthermore, circNFIB was identified as a miR-433 endogenous sponge. Overexpression of circNFIB could attenuate pro-proliferative effects induced by the miR-433 mimic while inhibition of circNFIB exhibited opposite results. Finally, upregulation of circNFIB also reversed the expression levels of target genes and downstream signaling pathways of miR-433. In conclusion, circNFIB is critical for protection against cardiac fibrosis. The circNFIB-miR-433 axis may represent a novel therapeutic approach for treatment of fibrotic diseases.
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Project description:Acute myocardial infarction (MI) due to coronary artery occlusion is accompanied by a pathological remodeling response that includes hypertrophic cardiac growth and fibrosis, which impair cardiac contractility. Previously, we showed that cardiac hypertrophy and heart failure are accompanied by characteristic changes in the expression of a collection of specific microRNAs (miRNAs), which act as negative regulators of gene expression. Here, we show that MI in mice and humans also results in the dysregulation of specific miRNAs, which are similar to but distinct from those involved in hypertrophy and heart failure. Among the MI-regulated miRNAs are members of the miR-29 family, which are down-regulated in the region of the heart adjacent to the infarct. The miR-29 family targets a cadre of mRNAs that encode proteins involved in fibrosis, including multiple collagens, fibrillins, and elastin. Thus, down-regulation of miR-29 would be predicted to derepress the expression of these mRNAs and enhance the fibrotic response. Indeed, down-regulation of miR-29 with anti-miRs in vitro and in vivo induces the expression of collagens, whereas over-expression of miR-29 in fibroblasts reduces collagen expression. We conclude that miR-29 acts as a regulator of cardiac fibrosis and represents a potential therapeutic target for tissue fibrosis in general.
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Project description:Circular RNAs (circRNAs), a subclass of noncoding RNAs, are reportedly involved in the progression of various diseases. However, the exact role of circRIMS1, also termed hsa_circ_0132246, in human bladder cancer remains unknown. By performing RNA sequencing comparing bladder cell lines and normal uroepithelial cells, circRIMS1 was selected as a research object. We further verified by qRT-PCR that circRIMS1 is upregulated in both bladder cancer tissue and cell lines. Proliferation, colony-formation, Transwell migration, invasion, apoptosis, western blotting, and in vivo experiments were utilized to clarify the roles of circRIMS1, microRNA (miR)-433-3p, and cell cycle and apoptosis regulator 1 (CCAR1). For mechanistic investigation, RNA pulldown, fluorescence in situ hybridization (FISH), and luciferase reporter assay confirmed the binding of circRIMS1 with miR-433-3p. Inhibition of circRIMS1 suppressed the proliferation, migration, and invasion of bladder cancer cells both in vitro and in vivo. Moreover, the circRIMS1/miR-433-3p/CCAR1 regulatory axis was confirmed to be responsible for the biological functions of circRIMS1. Taken together, our research demonstrated that circRIMS1 promotes tumor growth, migration, and invasion through the miR-433-3p/CCAR1 regulatory axis, representing a potential therapeutic target and biomarker in bladder cancer.
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