Abstract
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 HMGB2 overexpression. HMGB2 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 HMGB2 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 HMGB2, 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 HMGB2 expression using miRNA inhibitors represents a potential strategy to overcome the detrimental effects of cellular senescence in endothelial cells.
Highlights
IntroductionIn 1965, Hayflick et al first used the term “cellular senescence” to describe the limitations of normal human cell proliferation [1]
Received: 30 December 2021In 1965, Hayflick et al first used the term “cellular senescence” to describe the limitations of normal human cell proliferation [1]
As cell proliferation was found to slow down from PDL42 onwards, we considered that cellular senescence was initiated from this point for convenience
Summary
In 1965, Hayflick et al first used the term “cellular senescence” to describe the limitations of normal human cell proliferation [1]. Cellular senescence is characterized by a stable and irreversible cell cycle arrest, and is associated with multiple cellular and molecular changes. Cellular senescence can compromise tissue repair and regeneration, thereby contributing to aging. Removal of senescent cells can attenuate age-related tissue dysfunction and extend health span [2]. The causes of cellular senescence involve telomere shortening, DNA damage, oxidative stress, and oncogene activation [3]. Telomere shortening generated by repeated DNA replication is mainly responsible for replicative senescence [2,4]. DNA damage induced by radiation and reactive oxygen species resulting in double-stranded
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