Dysfunction of Endothelial Progenitor Cells from Smokers and Chronic Obstructive Pulmonary Disease Patients Due to Increased DNA Damage and Senescence

Authors

  • Koralia E. Paschalaki,

    1. Airway Disease Section and National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom
    2. Vascular Sciences, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom
    3. Histology-Embryology Department, Faculty of Medicine, University of Athens, Athens, Greece
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  • Richard D. Starke,

    1. Vascular Sciences, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom
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  • Yanhua Hu,

    1. Cardiovascular Division, King's College London British Heart Foundation Centre, London, United Kingdom
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  • Nicolas Mercado,

    1. Airway Disease Section and National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom
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  • Andriana Margariti,

    1. Cardiovascular Division, King's College London British Heart Foundation Centre, London, United Kingdom
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  • Vassilis G. Gorgoulis,

    1. Histology-Embryology Department, Faculty of Medicine, University of Athens, Athens, Greece
    2. Biomedical Research Foundation, Academy of Athens, Athens, Greece
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  • Anna M. Randi,

    1. Vascular Sciences, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom
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  • Peter J. Barnes

    Corresponding author
    1. Airway Disease Section and National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom
    • Correspondence: Peter J. Barnes, FRS, FMedSci, Airway Disease Section, National Heart & Lung Institute, Imperial College London, Dovehouse Street, London SW3 6LY, U.K. Telephone: +44(0)207 594 7959; Fax: +44(0)207 351 8126, e-mail: p.j.barnes@imperial.ac.uk

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  • Author contributions: K.E.P.: conception and design, provision of study material or patients, collection and/or assembly of data, data analysis and interpretation, and manuscript writing; R.D.S.: data analysis and interpretation and collection and/or assembly of data; Y.H., N.M., and A.M.: collection and/or assembly of data; V.G.G.: data analysis and interpretation; A.M.R.: conception and design, data analysis and interpretation, manuscript writing, and final approval of manuscript; P.J.B.: conception and design, financial support, provision of study material or patients, final approval of manuscript. *A.M.R. and P.J.B. share senior authorship.

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. Stem Cells 2013;31:2813–2826

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