title: Age intrinsic loss of telomere protection via TRF1 reduction in endothelial cells.
abstract: Aging is a major factor predisposing for multiple diseases. Telomeres at the ends of chromosomes protect the integrity of chromosomal DNA. A specialized six-protein complex termed shelterin protects the telomere from unwanted interaction with DNA damage pathways. The aim of our study was to evaluate the integrity of telomeres and the stability of telomere protection during aging in endothelial cells (EC). We describe that aging EC can be characterized by an increased cell size (40%, p=0.02) and increased expression of PAI 1 (4 fold, p=0.02), MCP1 (10 fold, p=0.001) and GMCSF (15 fold, p=0.004). Telomeric state in aging cells is defined by an increased telomere oxidation (27%, p=0.01), reduced telomere length (62%, p=0.02), and increased DNA damage foci formation (5% in young EC versus 16% in aged EC, p=0.003). This telomeric dysfunction is accompanied by a reduction in the shelterin component TRF1 (33% mRNA, p=0.001; 24% protein, p=0.007). Overexpression of TRF1 in aging EC reduced telomere-associated DNA damage foci to 5% (p=0.02) and reduced expression levels of MCP1 (18% reduction, p=0.008). Aged EC have increased telomere damage and an intrinsic loss of telomere protection. Reestablishing telomere integrity could therefore be a target for rejuvenating endothelial cell function.
authors.affiliation: Department of Internal Medicine II, Cardiology, Medical University of Vienna, Vienna, Austria. Electronic address: philipp.hohensinner@meduniwien.ac.at.
authors.forename: P J
authors.initials: PJ
authors.lastname: Hohensinner
authors.affiliation: Department of Internal Medicine II, Cardiology, Medical University of Vienna, Vienna, Austria.
authors.forename: C
authors.initials: C
authors.lastname: Kaun
authors.affiliation: Department of Surgery, Medical University of Vienna, Vienna, Austria.
authors.forename: E
authors.initials: E
authors.lastname: Buchberger
authors.affiliation: Department of Internal Medicine II, Cardiology, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Cluster for Cardiovascular Research, Vienna, Austria.
authors.forename: B
authors.initials: B
authors.lastname: Ebenbauer
authors.affiliation: Department of Internal Medicine II, Cardiology, Medical University of Vienna, Vienna, Austria; Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: S
authors.initials: S
authors.lastname: Demyanets
authors.affiliation: Department of Surgery, Division of Vascular Surgery, Medical University of Vienna, Vienna, Austria.
authors.forename: I
authors.initials: I
authors.lastname: Huk
authors.affiliation: Department of Gynecology, Medical University of Vienna, Vienna, Austria.
authors.forename: W
authors.initials: W
authors.lastname: Eppel
authors.affiliation: Department of Internal Medicine II, Cardiology, Medical University of Vienna, Vienna, Austria.
authors.forename: G
authors.initials: G
authors.lastname: Maurer
authors.affiliation: Ludwig Boltzmann Cluster for Cardiovascular Research, Vienna, Austria; 3rd Medical Department, Wilhelminenhospital, Vienna, Austria.
authors.forename: K
authors.initials: K
authors.lastname: Huber
authors.affiliation: Department of Internal Medicine II, Cardiology, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Cluster for Cardiovascular Research, Vienna, Austria; Core Facilities, Medical University of Vienna, Vienna, Austria.
authors.forename: J
authors.initials: J
authors.lastname: Wojta
mesh_terms: D015153:Blotting, Western; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics*; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D015870:Gene Expression; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D018613:Microscopy, Confocal; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016615:Telomere / Q000235:genetics* / Q000378:metabolism; D035321:Telomeric Repeat Binding Protein 1 / Q000235:genetics* / Q000378:metabolism
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human; D035321:Telomeric Repeat Binding Protein 1; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: Aging; DNA damage; Senescence; Shelterin; Telomere dysfunction