Jo Hye-Ram, Hwang Jiwon, Jeong Jae-Hoon
Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Science, Seoul, 01812, South Korea.
Radiological and Medico-Oncological Sciences, University of Science and Technology, Daejeon, 34113, South Korea.
Noncoding RNA Res. 2023 May 18;8(3):385-391. doi: 10.1016/j.ncrna.2023.05.002. eCollection 2023 Sep.
During cellular senescence, irreversible cell cycle arrest is accompanied by morphological and genetic alterations. MicroRNAs (miRNAs) play a critical role in regulating senescence by modulating the abundance of crucial senescence regulatory proteins. Therefore, to identify novel senescence-associated miRNAs, we analyzed differentially expressed miRNAs in microvascular endothelial cells (MVEC). Among the 80 differentially expressed miRNAs in replicative senescent MVECs, 16 miRNAs of unknown gene ontology were used in the senescence-associated β-galactosidase assay. Thus, we identified miR-214-5p as having high senescence-inducing activity, inhibiting the proliferation and angiogenesis activity of MVECs. To reveal the senescence-regulating mechanism of miR-214-5p, we searched for target genes through sequence- and literature-based analysis. Molecular manipulation of miR-214-5p demonstrated that miR-214-5p regulated the expression and function of Jagged 1 (JAG1) in senescent MVECs. Silencing or downstream genes of JAG1-Notch signaling, accelerated the senescence of MVECs. Additionally, ectopic overexpression of JAG1 reversed the senescence-inducing activity of miR-214-5p. In conclusion, we identified miR-214-5p as a senescence-associated miRNA. Targeting miR-214-5p may be a potential strategy to delay vascular aging and overcome the detrimental effects of senescence and age-related diseases.
在细胞衰老过程中，不可逆的细胞周期停滞伴随着形态和基因改变。微小RNA（miRNA）通过调节关键衰老调节蛋白的丰度在调节衰老中起关键作用。因此，为了鉴定新的衰老相关miRNA，我们分析了微血管内皮细胞（MVEC）中差异表达的miRNA。在复制性衰老的MVEC中80个差异表达的miRNA中，16个基因本体未知的miRNA用于衰老相关β-半乳糖苷酶检测。因此，我们鉴定出miR-214-5p具有高衰老诱导活性，可抑制MVEC的增殖和血管生成活性。为了揭示miR-214-5p的衰老调节机制，我们通过基于序列和文献的分析来寻找靶基因。对miR-214-5p的分子操作表明，miR-214-5p在衰老的MVEC中调节Jagged 1（JAG1）的表达和功能。沉默JAG1-Notch信号的下游基因会加速MVEC的衰老。此外，JAG1的异位过表达逆转了miR-214-5p的衰老诱导活性。总之，我们鉴定出miR-214-5p是一种衰老相关的miRNA。靶向miR-214-5p可能是延缓血管衰老以及克服衰老和年龄相关疾病有害影响的潜在策略。
