Sirtuin 6 deficiency induces endothelial cell senescence via downregulation of forkhead box M1 expression

Ok Hee Lee, Yun Mi Woo, Sohyeon Moon, Jihyun Lee, Haeun Park, Hoon Jang, Yun Yong Park, Soo Kyung Bae, Keun Hong Park, Ji Hoe Heo, Youngsok Choi

Research output: Contribution to journalArticlepeer-review

23 Citations (Scopus)


Cellular senescence of endothelial cells causes vascular dysfunction, promotes atherosclerosis, and contributes to the development of age-related vascular diseases. Sirtuin 6 (SIRT6), a conserved NAD+-dependent protein deacetylase, has beneficial effects against aging, despite the fact that its functional mechanisms are largely uncharacterized. Here, we show that SIRT6 protects endothelial cells from senescence. SIRT6 expression is progressively decreased during both oxidative stress-induced senescence and replicative senescence. SIRT6 deficiency leads to endothelial dysfunction, growth arrest, and premature senescence. Using genetically engineered endothelial cell-specific SIRT6 knockout mice, we also show that down-regulation of SIRT6 expression in endothelial cells exacerbates vascular aging. Expression microarray analysis demonstrated that SIRT6 modulates the expression of multiple genes involved in cell cycle regulation. Specifically, SIRT6 appears to regulate the expression of forkhead box M1 (FOXM1), a critical transcription factor for cell cycle progression and senescence. Overexpression of FOXM1 ameliorates SIRT6 deficiency-induced endothelial cell senescence. In this work, we demonstrate the role of SIRT6 as an anti-aging factor in the vasculature. These data may provide the basis for future novel therapeutic approaches against age-related vascular disorders.

Original languageEnglish
Pages (from-to)20946-20967
Number of pages22
Issue number21
Publication statusPublished - 2020 Nov

Bibliographical note

Publisher Copyright:
© 2020 Lee et al.

All Science Journal Classification (ASJC) codes

  • Ageing
  • Cell Biology


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