title: Donepezil attenuates high glucose-accelerated senescence in human umbilical vein endothelial cells through SIRT1 activation.
abstract: Cellular senescence of endothelial cells is a damage and stress response which induces pro-inflammatory, pro-atherosclerotic, and pro-thrombotic phenotypes. Donepezil is a drug used for the treatment of mild to moderate dementia of the Alzheimer's disease (AD). The aim of the present study was to investigate the attenuation of endothelial cell senescence by donepezil and to explore the mechanisms underlying the anti-aging effects of donepezil. Our results indicated that high glucose (HG) markedly decreased cell viability of human umbilical vein endothelial cells (HUVECs), and this phenomenon was reversed by treatment with donepezil. Importantly, our results displayed that the frequency of senescent (SA-ß-gal-positive) cells and the expression level of senescence genes (PAI-1 and p21) were significantly higher in the HG group compared with the normal glucose (NG) group, and these changes were blocked by treatment with donepezil. Also, our results showed that donepezil inhibits the generation of reactive oxygen species (ROS), which promotes cellular senescence. Pretreatment with nicotinamide (NAM), a sirtuin 1 (SIRT1) inhibitor, inhibited the reduction in senescence associated with donepezil. Indeed, our results indicated that donepezil increased the SIRT1 enzyme activity. Therefore, these results show that donepezil delays cellular senescence that is promoted under HG condition via activation of SIRT1.
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, No. 28, Fuxing Rd., Haidian District, Beijing, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.forename: Feng
authors.initials: F
authors.lastname: Tian
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Shanshan
authors.initials: S
authors.lastname: Zhou
authors.forename: Xueqing
authors.initials: X
authors.lastname: Dong
authors.forename: Kai
authors.initials: K
authors.lastname: Guo
authors.forename: Jing
authors.initials: J
authors.lastname: Jing
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhou
authors.forename: Yundai
authors.initials: Y
authors.lastname: Chen
mesh_terms: D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D000077265:Donepezil; D005947:Glucose / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007189:Indans / Q000494:pharmacology*; D009536:Niacinamide; D010880:Piperidines / Q000494:pharmacology*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D056564:Sirtuin 1 / Q000378:metabolism
chemical_list: D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D017395:Plasminogen Activator Inhibitor 1; D017382:Reactive Oxygen Species; C051321:SERPINE1 protein, human; D009536:Niacinamide; D000077265:Donepezil; D056564:Sirtuin 1; D005947:Glucose