MicroRNA miR-214-5p induces senescence of microvascular endothelial cells by targeting the JAG1/Notch signaling pathway

Hye-Ram Jo; Jiwon Hwang; Jae-Hoon Jeong

doi:10.1016/j.ncrna.2023.05.002

MicroRNA miR-214-5p induces senescence of microvascular endothelial cells by targeting the JAG1/Notch signaling pathway

Noncoding RNA Res. 2023 May 18;8(3):385-391. doi: 10.1016/j.ncrna.2023.05.002. eCollection 2023 Sep.

Authors

Hye-Ram Jo^{1

2}, Jiwon Hwang^{1

3}, Jae-Hoon Jeong^{1

2}

Affiliations

¹ Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Science, Seoul, 01812, South Korea.
² Radiological and Medico-Oncological Sciences, University of Science and Technology, Daejeon, 34113, South Korea.
³ Department of Life Sciences, Korea University, Seoul, 02841, South Korea.

Abstract

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 JAG1 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.

Keywords: Jagged1; Microvascular endothelial cell; Notch signaling; Senescence; miR-214-5p; microRNA.