Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Science, Seoul 01812, Korea.
Radiological and Medico-Oncological Sciences, University of Science and Technology, Daejeon 34113, Korea.
Cells. 2022 Feb 8;11(3):584. doi: 10.3390/cells11030584.
High mobility group box 2 (HMGB2) is a non-histone chromosomal protein involved in various biological processes, including cellular senescence. However, its role in cellular senescence has not been evaluated extensively. To determine the regulatory role and mechanism of HMGB2 in cellular senescence, we performed gene expression analysis, senescence staining, and tube formation assays using young and senescent microvascular endothelial cells (MVECs) after small RNA treatment or overexpression. expression decreased with age and was regulated at the transcriptional level. siRNA-mediated downregulation inhibited cell proliferation and accelerated cellular senescence. In contrast, ectopic overexpression delayed senescence and maintained relatively higher tube-forming activity. To determine the downregulation mechanism, we screened miRNAs that were significantly upregulated in senescent MVECs and selected HMGB2-targeting miRNAs. Six miRNAs, miR-23a-3p, 23b-3p, -181a-5p, -181b-5p, -221-3p, and -222-3p, were overexpressed in senescent MVECs. Ectopic introduction of miR-23a-3p, -23b-3p, -181a-5p, -181b-5p, and -221-3p, with the exception of miR-222-3p, led to the downregulation of , upregulation of senescence-associated markers, and decreased tube formation activity. Inhibition of miR-23a-3p, -181a-5p, -181b-5p, and -221-3p delayed cellular senescence. Restoration of expression using miRNA inhibitors represents a potential strategy to overcome the detrimental effects of cellular senescence in endothelial cells.
高迁移率族蛋白 B2（HMGB2）是一种非组蛋白染色体蛋白，参与多种生物学过程，包括细胞衰老。然而，其在细胞衰老中的作用尚未得到广泛评估。为了确定 HMGB2 在细胞衰老中的调节作用和机制，我们使用小 RNA 处理或过表达后年轻和衰老的微血管内皮细胞（MVEC）进行基因表达分析、衰老染色和管形成测定。HMGB2 的表达随年龄增长而降低，并受转录水平调控。siRNA 介导的下调抑制细胞增殖并加速细胞衰老。相比之下，异位过表达延缓衰老并维持相对较高的管形成活性。为了确定 HMGB2 的下调机制，我们筛选了在衰老 MVEC 中显著上调的 miRNA，并选择了 HMGB2 靶向 miRNA。miR-23a-3p、23b-3p、-181a-5p、-181b-5p、-221-3p 和 -222-3p 这 6 种 miRNA 在衰老 MVEC 中过表达。在衰老 MVEC 中过表达 miR-23a-3p、23b-3p、-181a-5p、-181b-5p 和 -221-3p，但 miR-222-3p 除外，导致 HMGB2 下调、衰老相关标志物上调和管形成活性降低。抑制 miR-23a-3p、-181a-5p、-181b-5p 和 -221-3p 可延缓细胞衰老。使用 miRNA 抑制剂恢复 HMGB2 表达可能是克服内皮细胞衰老有害影响的一种潜在策略。
