The First Clinical College, Guangdong Medical University, Zhanjiang 524000, Guangdong, PR China.
Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, PR China.
Int J Biol Macromol. 2023 Dec 31;253(Pt 4):126953. doi: 10.1016/j.ijbiomac.2023.126953. Epub 2023 Sep 20.
Long intergenic non-coding RNA 00657 (linc00657) is involved in various diseases, whereas its role in atherosclerosis (AS) development remains inconclusive. This study was designed to investigate the effects and underlying mechanisms of linc00657 in atherogenesis. The results showed that ox-LDL treatment significantly induced pyroptosis in human THP-1-derived macrophages. The secretion levels of LDH and pro-inflammatory factors were markedly enhanced, and the integrity of plasma membranes was disrupted in ox-LDL-treated THP-1-derived macrophages. These effects were significantly compensated after transfection with linc00657 siRNA and became more evident by linc00657 overexpression. Moreover, the effects of linc00657 overexpression on pyroptosis of THP-1-derived macrophages can also be robustly reversed by TXNIP knockdown or miR-106b-5p mimics transfection. Mechanistically, linc00657 enhanced TXNIP expression by competitively binding to miR-106b-5p, promoting NLRP3 inflammasome activation. Finally, we found that linc00657 overexpression significantly increased the expression of pyroptosis-related factors and decreased miR-106b-5p level in the aorta of high-fat-diet-fed apoE mice. Furthermore, linc00657 up-regulation enlarged the plaque area, exacerbated plasma lipid profile, and increased pro-inflammatory cytokines levels in the serum, effects that were reversed by injection of miR-106b-5p agomir. This evidence indicated that linc00657 stimulated macrophage pyroptosis and aggravated the progression of AS via the miR-106b-5p/TXNIP/NLRP3 pathway.
长链非编码 RNA 00657（linc00657）参与多种疾病，但其在动脉粥样硬化（AS）发展中的作用尚不清楚。本研究旨在探讨 linc00657 在动脉粥样形成中的作用及其潜在机制。结果表明，ox-LDL 处理可显著诱导人 THP-1 衍生巨噬细胞发生细胞焦亡。ox-LDL 处理的 THP-1 衍生巨噬细胞中 LDH 和促炎因子的分泌水平显著升高，质膜完整性受到破坏。用 linc00657 siRNA 转染后，这些作用明显得到补偿，而过表达 linc00657 则更为明显。此外，linc00657 过表达对 THP-1 衍生巨噬细胞细胞焦亡的作用也可以通过 TXNIP 敲低或 miR-106b-5p 模拟物转染得到强有力的逆转。机制上，linc00657 通过与 miR-106b-5p 竞争结合来增强 TXNIP 的表达，从而促进 NLRP3 炎性小体的激活。最后，我们发现 linc00657 过表达可显著增加高脂饮食喂养的 apoE 小鼠主动脉中细胞焦亡相关因子的表达，降低 miR-106b-5p 水平。此外，linc00657 的上调增加了斑块面积，加剧了血脂谱，并增加了血清中促炎细胞因子的水平，这些作用可通过注射 miR-106b-5p 激动剂得到逆转。这些证据表明，linc00657 通过 miR-106b-5p/TXNIP/NLRP3 途径刺激巨噬细胞细胞焦亡，加重 AS 的进展。
