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.
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References
Alster O, Korwek Z (2014) Markers of cellular senescence. Postepy Biochem 60(2):138–46
Arunachalam G, Samuel SM, Marei I, Ding H, Triggle CR (2014) Metformin modulates hyperglycaemia-induced endothelial senescence and apoptosis through SIRT1. Br J Pharmacol 171(2):523–35
Behrendt D, Ganz P (2002) Endothelial function. From vascular biology to clinical applications. Am J Cardiol 90:40L–48L
Ben-Porath I, Weinberg RA (2005) The signals and pathways activating cellular senescence. Int J Biochem Cell Biol 37:961–976
Bhutada P, Mundhada Y, Bansod K et al (2011) Protection of cholinergic and antioxidant system contributes to the effect of berberine ameliorating memory dysfunction in rat model of streptozotocin-induced diabetes. Behav Brain Res 220(1):30–41
Brunet A, Sweeney LB, Sturgill JF et al (2004) Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303:2011–2015
Burrig KF (1991) The endothelium of advanced arteriosclerotic plaques in humans. Arterioscler Thromb 11:1678–1689
Corella D, Ordovás JM (2014) Aging and cardiovascular diseases: The role of gene-diet interactions. Ageing Res Rev 18C:53–73
Dimri GP, Lee X, Basile G et al (1995) A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci U S A 92:9363–9367
Frippiat C, Chen QM, Zdanov S, Magalhaes JP, Remacle J, Toussaint O (2001) Subcytotoxic H2O2 stress triggers a release of transforming growth factor-beta 1, which induces biomarkers of cellular senescence of human diploid fibroblasts. J Biol Chem 276:2531–2537
Gorbunova V, Seluanov A, Pereira-Smith OM (2002) Expression of human telomerase (hTERT) does not prevent stress-induced senescence in normal human fibroblasts but protects the cells from stress-induced apoptosis and necrosis. J Biol Chem 277:38540–38549
Ho KK, Myatt SS, Lam EW (2008) Many forks in the path: cycling with FoxO. Oncogene 27:2300–2311
Hwang J, Hwang H, Lee HW et al (2010) Microglia signaling as a target of donepezil. Neuropharmacology 58:1122e1129
Lakatta EG, Levy D (2003) Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: part I: aging arteries: a ‘set up’ for vascular disease. Circulation 107:139–146
Kamat PK, Tota S, Saxena G et al (2010) Okadaic acid (ICV) induced memory impairment in rats: a suitable experimental model to test anti-dementia activity. Brain Res 1309:66–74
Luo J, Nikolaev AY, Imai S et al (2001) Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell 107:137–148
Mattagajasingh I, Kim CS, Naqvi A et al (2007) SIRT1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide synthase. Proc Natl Acad Sci U S A 104:14855–14860
Mhaidat NM, Zhang XD, Allen J et al (2007) Temozolomide induces senescence but not apoptosis in human melanoma cells. Br J Cancer 97(9):1225–33
Minamino T, Miyauchi H, Yoshida T et al (2002) Endothelial cell senescence in human atherosclerosis: role of telomere in endothelial dysfunction. Circulation 105:1541–1544
Okatani Y, Wakatsuki A, Reiter RJ (2000) Protective effect of melatonin against homocysteine-induced vasoconstriction of human umbilical artery. Biochem Biophys Res Commun 277:470–475
Ota H, Akishita M, Eto M et al (2007) (2007) Sirt1 modulates premature senescence-like phenotype in human endothelial cells. J Mol Cell Cardiol 43:571–579
Ota H, Tokunaga E, Chang K et al (2006) Sirt1 inhibitor, Sirtinol, induces senescence-like growth arrest with attenuated Ras-MAPK signaling in human cancer cells. Oncogene 25:176–185
Potente M, Ghaeni L, Baldessari D et al (2007) SIRT1 controls endothelial angiogenic functions during vascular growth. Genes Dev 21:2644–2658
Reale M, Iarlori C, Gambi F et al (2005) Acetylcholinesterase inhibitors effects on oncostatin-M, interleukin-1 beta and interleukin-6 release from lymphocytes of Alzheimer’s disease patients. Exp Gerontol 40(3):165–71
Rogers SC, Zhang X, Azhar G et al (2013) Exposure to high or low glucose levels accelerates the appearance of markers of endothelial cell senescence and induces dysregulation of nitric oxide synthase. J Gerontol A Biol Sci Med Sci 68:1469–1481
Saxena G, Patro IK, Nath C (2011) ICV STZ induced impairment in memory and neuronal mitochondrial function: a protective role of nicotinic receptor. Behav Brain Res 224(1):50–7
Sharifipour M, Izadpanah E, Nikkhoo B et al (2014) A new pharmacological role for donepezil: attenuation of morphine-induced tolerance and apoptosis in rat central nervous system. J Biomed Sci 21:6
Sniderman AD, Furberg CD (2008) Age as a modifiable risk factor for cardiovascular disease. Lancet 371:1547–1549
Yanaka M, Honma T, Sato K et al (2011) Increased monocytic adhesion by senescence in human umbilical vein endothelial cells. Biosci Biotechnol Biochem 75:1098–1103
Yoshiyama Y, Kojima A, Ishikawa C, Arai K (2010) Anti-inflammatory action of donepezil ameliorates tau pathology, synaptic loss, and neurodegeneration in a tauopathy mouse model. J Alzheimers Dis 22:295–306
Zdanov S, Debacq-Chainiaux F, Toussaint O (2007) Knocking down p53 with siRNA does not affect the overexpression of p21WAF-1 after exposure of IMR-90 hTERT fibroblasts to a sublethal concentration of H2O2 leading to premature senescence. Ann N Y Acad Sci 1100:316–22
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This study was supported by the nursery fund of the Chinese PLA General Hospital.
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Zhang, T., Tian, F., Wang, J. et al. Donepezil attenuates high glucose-accelerated senescence in human umbilical vein endothelial cells through SIRT1 activation. Cell Stress and Chaperones 20, 787–792 (2015). https://doi.org/10.1007/s12192-015-0601-4
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DOI: https://doi.org/10.1007/s12192-015-0601-4