RESUMEN
Myofibroblasts predominantly emerging through fibroblast-to-myofibroblast transition (FMT) are considered to be the key collagen-producing cells in pulmonary fibrosis. Circular RNAs (circRNAs) are important players involved in many biological processes. circHIPK3 has been identified as the one of the most abundant circRNAs in human lung. In this study, we characterized the role of circHIPK3 in pulmonary fibrosis. We revealed that circHIPK3 is upregulated in bleomycin-induced pulmonary fibrosis mice model, FMT-derived myofibroblasts. circHIPK3 silencing can ameliorate FMT and suppress fibroblast proliferation in vivo and vitro. Fundamentally, circHIPK3 regulates FMT by functioning as an endogenous miR-338-3p sponge and inhibit miR-338-3p activity, thereby leading to increased SOX4 and COL1A1 expression. Moreover, dysregulated circHIPK3 expression was detected in the clinical samples of patients with idiopathic pulmonary fibrosis. Intervention of circHIPK3 may represent a promising therapy for pulmonary fibrosis.
Asunto(s)
Fibroblastos/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Miofibroblastos/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Fibrosis Pulmonar/genética , ARN Circular/metabolismo , Animales , Diferenciación Celular/genética , Proliferación Celular/genética , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Cadena alfa 1 del Colágeno Tipo I , Modelos Animales de Enfermedad , Células HEK293 , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Pulmón/citología , Pulmón/metabolismo , Ratones , Ratones Endogámicos C57BL , MicroARNs/genética , MicroARNs/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Fibrosis Pulmonar/metabolismo , ARN Circular/antagonistas & inhibidores , ARN Circular/genética , Factores de Transcripción SOXC/genética , Factores de Transcripción SOXC/metabolismo , Regulación hacia ArribaRESUMEN
AIMS: To determine whether use of radiofrequency catheter ablation (RFCA) combined with intravenously administered liposomal doxorubicin (L-DOX) facilitates a reduction in the recovery of post-ablation electrical conduction. METHODS: Circumferential ablation was performed on the epicardial surface of the left atrial appendage (LAA) in New Zealand White rabbits, and L-DOX was then administered intravenously. Fluorescence spectrophotometry was used to assess reagent bio-distribution, while Western blots and immunohistochemistry were used to assess the localization of the apoptotic markers Bcl-2, Bax, and cleaved CASP3 in the LAA. Liver, kidney, and cardiac functions were also measured to evaluate the safety of this approach. RESULTS: At 1 week and 1 month after RFCA, a pacing electrocardiogram could not be detected in most of the rabbits that had received the combined RFCA and L-DOX therapy. L-DOX began to target the LAA on the second day after RFCA. L-DOX treatment increased the apoptosis of cardiomyocytes in the regions peripheral to the necrotic area induced by RFCA. Doxorubicin had some effect on liver and kidney function, but these effects were reversible and did not affect survival. CONCLUSION: The present results provide evidence that L-DOX treatment can reduce the recovery of electrical conduction after RFCA therapy owing to L-DOX-induced apoptosis of cardiomyocytes in the ablated area and the proximal transition zone of the LAA.