Dysfunction of endothelial progenitor cells from smokers and chronic obstructive pulmonary disease patients due to increased DNA damage and senescence
Author(s)
Type
Journal Article
Abstract
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 double‐strand breaks and senescence compared to nonsmokers. Senescence negatively correlated with the expression and activity of sirtuin‐1 (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 (KU‐55933) 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.
Date Issued
2013-12-01
Date Acceptance
2013-05-15
Citation
Stem Cells, 2013, 31 (12), pp.2813-2826
ISSN
1066-5099
Publisher
AlphaMed Press
Start Page
2813
End Page
2826
Journal / Book Title
Stem Cells
Volume
31
Issue
12
Copyright Statement
© AlphaMed Press 2013. This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Sponsor
British Heart Foundation
Medical Research Council (MRC)
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000327736000021&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Grant Number
FS/10/47/28393
G0600868
Subjects
Science & Technology
Life Sciences & Biomedicine
Cell & Tissue Engineering
Biotechnology & Applied Microbiology
Oncology
Cell Biology
Hematology
Endothelial progenitor cells
Smoking
DNA damage response
Sirtuin
Cellular senescence
Ataxia telangiectasia-mutated kinase
ONCOGENE-INDUCED SENESCENCE
PERIPHERAL-BLOOD
STEM-CELLS
PREMATURE SENESCENCE
THERAPEUTIC TARGETS
CELLULAR SENESCENCE
ARTERIAL STIFFNESS
OXIDATIVE STRESS
SIRT1
ATHEROSCLEROSIS
Publication Status
Published
Date Publish Online
2013-07-29