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@article{Paschalaki:2013:10.1002/stem.1488,
author = {Paschalaki, KE and Starke, RD and Hu, Y and Mercado, N and Margariti, A and Gorgoulis, VG and Randi, AM and Barnes, PJ},
doi = {10.1002/stem.1488},
journal = {Stem Cells},
pages = {2813--2826},
title = {Dysfunction of endothelial progenitor cells from smokers and chronic obstructive pulmonary disease patients due to increased DNA damage and senescence},
url = {http://dx.doi.org/10.1002/stem.1488},
volume = {31},
year = {2013}
}

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TY  - JOUR
AB  - Cardiovascular disease (CVD) is a major cause of death in smokers, particularly in those with chronic obstructive pulmonary disease (COPD). Circulating endothelial progenitor cells (EPC) are required for endothelial homeostasis, and their dysfunction contributes to CVD. To investigate EPC dysfunction in smokers, we isolated and expanded blood outgrowth endothelial cells (BOEC) from peripheral blood samples from healthy nonsmokers, healthy smokers, and COPD patients. BOEC from smokers and COPD patients showed increased DNA doublestrand breaks and senescence compared to nonsmokers. Senescence negatively correlated with the expression and activity of sirtuin1 (SIRT1), a protein deacetylase that protects against DNA damage and cellular senescence. Inhibition of DNA damage response by silencing of ataxia telangiectasia mutated (ATM) kinase resulted in upregulation of SIRT1 expression and decreased senescence. Treatment of BOEC from COPD patients with the SIRT1 activator resveratrol or an ATM inhibitor (KU55933) also rescued the senescent phenotype. Using an in vivo mouse model of angiogenesis, we demonstrated that senescent BOEC from COPD patients are dysfunctional, displaying impaired angiogenic ability and increased apoptosis compared to cells from healthy nonsmokers. Therefore, this study identifies epigenetic regulation of DNA damage and senescence as pathogenetic mechanisms linked to endothelial progenitors' dysfunction in smokers and COPD patients. These defects may contribute to vascular disease and cardiovascular events in smokers and could therefore constitute therapeutic targets for intervention.
AU  - Paschalaki,KE
AU  - Starke,RD
AU  - Hu,Y
AU  - Mercado,N
AU  - Margariti,A
AU  - Gorgoulis,VG
AU  - Randi,AM
AU  - Barnes,PJ
DO  - 10.1002/stem.1488
EP  - 2826
PY  - 2013///
SN  - 1066-5099
SP  - 2813
TI  - Dysfunction of endothelial progenitor cells from smokers and chronic obstructive pulmonary disease patients due to increased DNA damage and senescence
T2  - Stem Cells
UR  - http://dx.doi.org/10.1002/stem.1488
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000327736000021&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - https://stemcellsjournals.onlinelibrary.wiley.com/doi/full/10.1002/stem.1488
UR  - http://hdl.handle.net/10044/1/73784
VL  - 31
ER  -

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