Background

Chronic obstructive pulmonary disease (COPD) is a disease associated with accelerated aging that threatens the lives of people worldwide and imposes heavy social and economic burdens. Cellular senescence is commonly observed in COPD and contributes to aging-related diseases.

Purpose

To identify the possible molecular pathways modulating cellular senescence in COPD.

Methods

MiR-494-3p expression levels in COPD tissues, small airway epithelial cells (SAECs) and BEAS-2B cells were detected by qRT-PCR. After transfection with miR-494-3p mimic or inhibitor in COPD SAECs, miR-494-3p modulation of senescence markers and senescence-associated secretory phenotype (SASP) proteins was detected. A luciferase assay was employed to verify the direct binding of SIRT3 and miR-494-3p. VX745 and c-myc siRNA were used to investigate the regulation of p38MAPK and c-myc by miR-494-3p.

Results

As a result of oxidative stress, MiR-494-3p was increased via the p38MAPK-c-myc signaling pathway in the lung tissues and cells of patients with COPD, and the increase in miR-494-3p was accompanied by increases in senescence markers (p27, p21 and p16) and SASP proteins (IL-1β, TNF-α, MMP2 and MMP9). MiR-494-3p was directly bound to SIRT3 in SAECs and was involved in cellular senescence. The upregulation of miR-494-3p decreased SIRT3 expression while increasing p27 expression in SAECs. Inhibition of miR-494-3p in SAECs from COPD patients reduced cell cycle arrest and the expression of SASP proteins (IL-1β, TNF-α, MMP2 and MMP9).

Conclusion

MiR-494-3p expression can be induced by oxidative stress via the p38MAPK-c-myc signaling pathway, and miR-494-3p can directly bind to SIRT3 to reduce its expression, leading to increased cellular senescence and thereby contributing to COPD progression.

中文翻译：

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抑制miR-494-3p可减轻COPD患者原代上皮细胞中氧化应激诱导的细胞衰老和炎症

背景

慢性阻塞性肺疾病（COPD）是与衰老加速相关的疾病，威胁全世界人民的生命，并带来沉重的社会和经济负担。细胞衰老通常发生在COPD中，并导致与衰老相关的疾病。

目的

以确定可能的分子途径调节COPD中的细胞衰老。

方法

通过qRT-PCR检测COPD组织，小气道上皮细胞（SAEC）和BEAS-2B细胞中的MiR-494-3p表达水平。在COPD SAEC中用miR-494-3p模拟物或抑制剂转染后，检测到miR-494-3p调节衰老标记和衰老相关的分泌表型（SASP）蛋白。使用萤光素酶测定法来验证SIRT3和miR-494-3p的直接结合。使用VX745和c-myc siRNA来研究miR-494-3p对p38MAPK和c-myc的调控。

结果

由于氧化应激，COPD患者的肺组织和细胞中的miR-494-3p通过p38MAPK-c-myc信号通路增加，miR-494-3p的增加伴随衰老标记的增加（p27，p21和p16）和SASP蛋白（IL-1β，TNF-α，MMP2和MMP9）。MiR-494-3p在SAEC中直接与SIRT3结合，并参与细胞衰老。在SAEC中，miR-494-3p的上调降低了SIRT3的表达，同时增加了p27的表达。在COPD患者的SAEC中抑制miR-494-3p可降低细胞周期阻滞和SASP蛋白（IL-1β，TNF-α，MMP2和MMP9）的表达。

结论

MiR-494-3p的表达可以通过p38MAPK-c-myc信号转导途径被氧化应激诱导，miR-494-3p可以直接与SIRT3结合以降低其表达，从而导致细胞衰老增加，从而促进COPD进程。