Background: Cardiac fibrosis is a common pathological process of most cardiac diseases, which may result in cardiac function impairment. Long noncoding RNAs (lncRNAs) have been verified as crucial regulators of cardiac fibrosis. This study explored the function and molecular mechanism of PVT1 in cardiac fibrosis.
Methods: TGF-β1-exposed human cardiac fibroblasts (HCF-a) and isoproterenol (ISO)-treated mice were used as the in vitro and in vivo cardiac fibrosis models. PVT1, miR-145, and HCN1 expression was determined by quantitative RT-PCR. Cell proliferation was evaluated by CCK-8 and EdU fluorescence staining. α-SMA and collagen I expression was assessed by immunohistochemical staining and immunofluorescence staining. Protein levels of fibrosis-related factors were assessed by Western blotting. The interaction between miR-145 and PVT1/HCN1 was evaluated by dual luciferase assay. ChIP assay was used to validate the binding of CREB1 to the promoter of PVT1. Cardiac fibrosis in mice was observed by H&E and Masson's trichrome staining.
Results: PVT1 and HCN1 were up-regulated, while miR-145 was down-regulated in the cardiac fibrosis models. PVT1 knockdown restrained TGF-β1-induced proliferation and activation of HCF-a cells. CREB1 bound to the promoter of PVT1 and activated its transcription. Mechanistically, PVT1 enhanced HCN1 expression via sponging miR-145. Finally, silencing of PVT1 attenuated cardiac fibrosis via regulating miR-145/HCN1 axis in mice in vivo.
Conclusion: PVT1 contributed to cardiac fibrosis by increasing HCN1 expression via sponging miR-145, which suggested that targeting PVT1 may be a therapeutic option for cardiac fibrosis and cardiac diseases.
Keywords: CREB1; Cardiac fibrosis; HCN1; PVT1; miR-145.
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