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

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-kappa B signaling abolished the enhanced inflammatory responses in senescent ECs, while NF-kappa B nuclear translocation in response to TNF-alpha 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-kappa B 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.

Automated summary

Senescent endothelial cells play a causal role in atherosclerosis by increasing inflammation-mediated VCAM-1 induction, leading to enhanced monocyte adhesion. The NF-kappa B signaling pathway is crucial for regulating inflammatory responses in senescent endothelial cells, and this regulation is achieved through epigenetic alterations involving active histone H3 trimethylation on lysine 4.