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.
Highlights
Senescent vascular cells are detected in atherosclerotic lesion, and its involvement in the development of atherosclerosis has been revealed; whether and the mechanism by which endothelial cell (EC) senescence is causally implicated in atherosclerosis remains unclear
Aging is closely associated with the morbidity and mortality of atherosclerotic disease, and vascular aging has been considered to play a role in the progression of atherosclerosis
It has been reported that cellular senescence in ECs causes reduced vasodilation capacity and impaired neovessel formation, at least partially through reduction in endothelial NO synthase (eNOS) and Bcl-2 expression during a ging[28, 31]
Summary
Senescent vascular cells are detected in atherosclerotic lesion, and its involvement in the development of atherosclerosis has been revealed; 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 Tie[2] or vascular endothelial cadherin promoter. Senescent cell-depletion and senolytic agents that preferentially kill senescent cells improved physical function and showed beneficial effects in age-related diseases such as osteoarthritis and atherosclerosis[13,14,15]. These findings strongly suggest the critical and causative role of cellular senescence in age-related diseases. By utilizing the unique endothelial progeroid mice, we identified EC senescence promotes atherosclerosis potentially through EC hyper-inflammability due to epigenetic alteration
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