Priority Research Paper Volume 12, Issue 21 pp 20946—20967
Sirtuin 6 deficiency induces endothelial cell senescence via downregulation of forkhead box M1 expression
- 1 Department of Biomedical Science, CHA University, Seongnam-si 13488, Gyeonggi-do, Republic of Korea
- 2 Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul 05029, Republic of Korea
- 3 Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Republic of Korea
- 4 Department of Dental Pharmacology, BK21 PLUS Project, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
- 5 Department of Neurology, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
- 6 Department of Life Science, Jeonbuk National University, Jeonju-si 54896, Jeollabuk-do, Republic of Korea
Received: July 9, 2020 Accepted: October 5, 2020 Published: November 10, 2020https://doi.org/10.18632/aging.202176
How to Cite
Copyright: © 2020 Lee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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.
SIRT: sirtuin; FOXM1: forkhead box M1; IL: interleukin; eNOS: endothelial nitric oxide synthase; HUVEC: human umbilical vein endothelial cell; SA β-gal: senescence-associated β-galactosidase; PD: population doubling; PQ: paraquat dichloride x-hydrate; Chk: checkpoint kinase; EGM-2: endothelial growth medium-2; MOI: multiplicity of infection; DAPI: 4´,6-diamidino-2-phenylindole.