Cellular senescence promotes endothelial activation through epigenetic alteration, and consequently accelerates atherosclerosis

Abstract Senescent vascular cells are detected in atherosclerotic lesion, and its involvement in the development of atherosclerosis has been revealed; however, whether and the mechanism by which endothelial cell (EC) senescence is causally implicated in atherosclerosis remains unclear. We here inves...

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Autores principales:	Sakiko Honda, Koji Ikeda, Ryota Urata, Ekura Yamazaki, Noriaki Emoto, Satoaki Matoba
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8a34ecd3f6314f959460d8035c051b9c
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spelling	oai:doaj.org-article:8a34ecd3f6314f959460d8035c051b9c2021-12-02T16:08:07ZCellular senescence promotes endothelial activation through epigenetic alteration, and consequently accelerates atherosclerosis10.1038/s41598-021-94097-52045-2322https://doaj.org/article/8a34ecd3f6314f959460d8035c051b9c2021-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-94097-5https://doaj.org/toc/2045-2322Abstract Senescent vascular cells are detected in atherosclerotic lesion, and its involvement in the development of atherosclerosis has been revealed; however, whether and the mechanism by which endothelial cell (EC) senescence is causally implicated in atherosclerosis remains unclear. We here investigate a role of EC senescence in atherosclerosis by utilizing EC-specific progeroid mice that overexpress the dominant negative form of telomeric repeat-binding factor 2 under the control of the Tie2 or vascular endothelial cadherin promoter. EC-specific progeria accelerated atherosclerosis in mice with target deletion of ApoE. Mechanistically, senescent ECs were markedly sensitive for inflammation-mediated VCAM-1 induction, leading to enhanced monocyte adhesion. Inhibition of NF-κB signaling abolished the enhanced inflammatory responses in senescent ECs, while NF-κB nuclear translocation in response to TNF-α were similar between young and senescent ECs. We found a higher association of VCAM-1 gene with active histone H3 trimethylated on lysine 4, leading to increased NF-κB accessibility in senescent ECs. Our data revealed that EC cellular senescence causes endothelial hyper-inflammability through epigenetic alteration, which consequently accelerates atherosclerosis. Therefore, EC senescence is a promising therapeutic target for the prevention and/or treatment of atherosclerotic disease in elderly population.Sakiko HondaKoji IkedaRyota UrataEkura YamazakiNoriaki EmotoSatoaki MatobaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sakiko Honda Koji Ikeda Ryota Urata Ekura Yamazaki Noriaki Emoto Satoaki Matoba Cellular senescence promotes endothelial activation through epigenetic alteration, and consequently accelerates atherosclerosis
description	Abstract Senescent vascular cells are detected in atherosclerotic lesion, and its involvement in the development of atherosclerosis has been revealed; however, whether and the mechanism by which endothelial cell (EC) senescence is causally implicated in atherosclerosis remains unclear. We here investigate a role of EC senescence in atherosclerosis by utilizing EC-specific progeroid mice that overexpress the dominant negative form of telomeric repeat-binding factor 2 under the control of the Tie2 or vascular endothelial cadherin promoter. EC-specific progeria accelerated atherosclerosis in mice with target deletion of ApoE. Mechanistically, senescent ECs were markedly sensitive for inflammation-mediated VCAM-1 induction, leading to enhanced monocyte adhesion. Inhibition of NF-κB signaling abolished the enhanced inflammatory responses in senescent ECs, while NF-κB nuclear translocation in response to TNF-α were similar between young and senescent ECs. We found a higher association of VCAM-1 gene with active histone H3 trimethylated on lysine 4, leading to increased NF-κB accessibility in senescent ECs. Our data revealed that EC cellular senescence causes endothelial hyper-inflammability through epigenetic alteration, which consequently accelerates atherosclerosis. Therefore, EC senescence is a promising therapeutic target for the prevention and/or treatment of atherosclerotic disease in elderly population.
format	article
author	Sakiko Honda Koji Ikeda Ryota Urata Ekura Yamazaki Noriaki Emoto Satoaki Matoba
author_facet	Sakiko Honda Koji Ikeda Ryota Urata Ekura Yamazaki Noriaki Emoto Satoaki Matoba
author_sort	Sakiko Honda
title	Cellular senescence promotes endothelial activation through epigenetic alteration, and consequently accelerates atherosclerosis
title_short	Cellular senescence promotes endothelial activation through epigenetic alteration, and consequently accelerates atherosclerosis
title_full	Cellular senescence promotes endothelial activation through epigenetic alteration, and consequently accelerates atherosclerosis
title_fullStr	Cellular senescence promotes endothelial activation through epigenetic alteration, and consequently accelerates atherosclerosis
title_full_unstemmed	Cellular senescence promotes endothelial activation through epigenetic alteration, and consequently accelerates atherosclerosis
title_sort	cellular senescence promotes endothelial activation through epigenetic alteration, and consequently accelerates atherosclerosis
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/8a34ecd3f6314f959460d8035c051b9c
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Cellular senescence promotes endothelial activation through epigenetic alteration, and consequently accelerates atherosclerosis

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