RESUMEN
Circular RNAs (circRNAs) regulate the expression of genes that are critical for various biological and pathological processes. Previous studies have reported that the expression of hsa_circ_0058092 is decreased in patients with diabetes mellitus (DM); however, the specific role of this circRNA in DM is unknown. In the present study, endothelial progenitor cells (EPCs) were isolated and a decreased hsa_circ_0058092 expression was found under conditions of hyperglycemia (HG). The overexpression of hsa_circ_0058092 protected the EPCs against HGinduced damage by preserving cell survival, proliferation, migration and angiogenic differentiation. The overexpression of hsa_circ_0058092 also decreased the HGinduced increase in NADPHoxidase proteins and inflammatory cytokines. Further investigation revealed that the overexpression of hsa_circ_0058092 enhanced FOXO3 expression, which was mediated through the interaction with miR217. Furthermore, the upregulation of miR217 or the downregulation of FOXO3 abolished the protective effects of hsa_circ_0058092 against HGinduced EPC damage. On the whole, these data suggest that hsa_circ_0058092 acts via the miR217/FOXO3 pathway to protect against EPCs HGinduced damage, and to preserve the migration and angiogenesis of EPCs.
Asunto(s)
Células Progenitoras Endoteliales/patología , Proteína Forkhead Box O3/genética , Hiperglucemia/genética , MicroARNs/genética , ARN Circular/genética , Movimiento Celular , Proliferación Celular , Células Cultivadas , Regulación hacia Abajo , Células Progenitoras Endoteliales/metabolismo , Humanos , Hiperglucemia/patología , Regulación hacia ArribaRESUMEN
Diabetes mellitus (DM) is a chronic, multifactorial metabolic disease whereby insulin deficiency or resistance results in hyperglycemia. A sustained high glucose environment results in inflammation and endothelial cell dysfunction. However, the underlying mechanisms are still not entirely clear. Circular RNAs (circRNAs) are recognized as functional non-coding RNAs involved in diverse biological processes, including DM. Previous studies have found that hsa_circ_0068087 is increased in DM patients. In order to identify whether hsa_circ_0068087 plays a role in high glucose (HG)-induced inflammation and endothelial cell dysfunction Human Umbilical Vein Endothelial Cell (HUVECs), quantitative reverse transcription PCR (qRTPCR), tube formation assay, enzyme-linked immunosorbent assay (ELISA) and bifluorescein reporter experiments were employed in this study. The results showed that the expression of hsa_circ_0068087 was upregulated in HUVECs following increases in glucose. Knockdown of hsa_circ_0068087 suppressed HG-induced HUVEC dysfunction and inflammation by suppression of the TLR4/NF-κB/NLRP3 inflammasome signaling pathway. Downregulation of miR-197 reversed hsa_circ_0068087 silence-induced HUVEC dysfunction and inflammation in the HG condition. It was found that TLR4 was the target of miR-197 and that overexpression of TLR4 ameliorated miR-197-induced HUVEC dysfunction and inhibited inflammation in the HG condition. Bifluorescein report experiments confirmed that miR-197 is a potential target of hsa_circ_0068087 and that TLR4 is a potential miR-197 target. Taken together, these results suggest that downregulation of hsa_circ_0068087 ameliorates TLR4/NF-κB/NLRP3 inflammasome-mediated inflammation and endothelial cell dysfunction in the high glucose condition by sponging miR-197.