Cellular senescence promotes endothelial activation through epigenetic alteration, and consequently accelerates atherosclerosis.
Sci Rep
; 11(1): 14608, 2021 07 16.
Article
em En
| MEDLINE
| ID: mdl-34272458
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Senescência Celular
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Molécula 1 de Adesão de Célula Vascular
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Células Endoteliais
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Epigênese Genética
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Aterosclerose
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article