Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disease related to abnormal activation of fibroblast-like synovium cells (FLS) with apoptosis, inflammation, and oxidative damage. Circular RNA Sirt1 (circ-Sirt1) is an abundant circRNA, exerts the function in inhibiting inflammation. However, little is known about the roles of circ-Sirt1, if any, in RA. The present study aimed to investigate the biological roles and mechanism of circ-Sirt1 on cell inflammation in RA-FLS MH7A cell line. This study showed circ-Sirt1 inhibited the proliferation and induced apoptosis of MH7A cells. Overexpression of circ-Sirt1 decreased of the levels of interleukin (IL)-1β and IL-6, tumour necrosis factor (TNF)-α, and matrix matalloproteinases (MMP)-1 and MMP-3 in MH7A cells. In addition, overexpression of circ-Sirt1 increased the expression of Sirt1, Nrf2, HO-1, IκBα, GCLC and GCLM, and decreased the ratio of acetylated NF-κB to normal NF-κB, and the expression of AP-1, COX-2 and HMGB1. Moreover, the expression of Keap1 and the ratio of acetylated NF-κB to normal NF-κB were partially increased and the Nrf2 and Sirt1 were partially reduced by siSirt1. Additionally, circ-Sirt1 overexpression promoted the activation of Sirt1 signal pathways by upregulating miR-132. In conclusion, the protective effect of Circ-Sirt1 on MH7A depends on inhibiting cell proliferation, promoting apoptosis and miR-132-mediated Sirt1 pathway to reduce inflammation.

摘要

类风湿性关节炎 (RA) 是一种慢性炎症性疾病，与成纤维样滑膜细胞 (FLS) 的异常活化有关，伴有细胞凋亡、炎症和氧化损伤。环状RNA Sirt1（circ-Sirt1）是一种丰富的环状RNA，发挥抑制炎症的作用。然而，关于 circ-Sirt1（如果有的话）在 RA 中的作用知之甚少。本研究旨在探讨circ-Sirt1对RA-FLS MH7A细胞系炎症的生物学作用和机制。本研究表明 circ-Sirt1 抑制 MH7A 细胞的增殖并诱导其凋亡。circ-Sirt1 的过表达降低了 MH7A 细胞中白细胞介素 (IL)-1β 和 IL-6、肿瘤坏死因子 (TNF)-α 以及基质金属蛋白酶 (MMP)-1 和 MMP-3 的水平。此外，circ-Sirt1 的过表达增加了 Sirt1、Nrf2、HO-1、IκBα、GCLC 和 GCLM，并降低了乙酰化 NF-κB 与正常 NF-κB 的比例，以及 AP-1、COX-2 和 HMGB1 的表达。此外，通过 siSirt1，Keap1 的表达和乙酰化 NF-κB 与正常 NF-κB 的比率部分增加，Nrf2 和 Sirt1 部分降低。此外，circ-Sirt1 过表达通过上调 miR-132 促进了 Sirt1 信号通路的激活。总之，Circ-Sirt1对MH7A的保护作用取决于抑制细胞增殖、促进细胞凋亡和miR-132介导的Sirt1通路减轻炎症。Keap1 的表达和乙酰化 NF-κB 与正常 NF-κB 的比率部分增加，而 Nrf2 和 Sirt1 被 siSirt1 部分降低。此外，circ-Sirt1 过表达通过上调 miR-132 促进了 Sirt1 信号通路的激活。总之，Circ-Sirt1对MH7A的保护作用取决于抑制细胞增殖、促进细胞凋亡和miR-132介导的Sirt1通路减轻炎症。Keap1 的表达和乙酰化 NF-κB 与正常 NF-κB 的比率部分增加，而 Nrf2 和 Sirt1 被 siSirt1 部分降低。此外，circ-Sirt1 过表达通过上调 miR-132 促进了 Sirt1 信号通路的激活。总之，Circ-Sirt1对MH7A的保护作用取决于抑制细胞增殖、促进细胞凋亡和miR-132介导的Sirt1通路减轻炎症。