title: Age-dependent impairment of endothelial progenitor cells is corrected by growth-hormone-mediated increase of insulin-like growth-factor-1.
abstract: Aging is associated with an increased risk for atherosclerosis. A possible cause is low numbers and dysfunction of endothelial progenitor cells (EPC) which insufficiently repair damaged vascular walls. We hypothesized that decreased levels of insulin-like growth factor-1 (IGF-1) during age contribute to dysfunctional EPC. We measured the effect of growth hormone (GH), which increases endogenous IGF-1 levels, on EPC in mice and human subjects. We compared EPC number and function in healthy middle-aged male volunteers (57.4+/-1.4 years) before and after a 10 day treatment with recombinant GH (0.4 mg/d) with that of younger and elderly male subjects (27.5+/-0.9 and 74.1+/-0.9 years). Middle-aged and elderly subjects had lower circulating CD133(+)/VEGFR-2(+) EPC with impaired function and increased senescence. GH treatment in middle-aged subjects elevated IGF-1 levels (126.0+/-7.2 ng/mL versus 241.1+/-13.8 ng/mL; P<0.0001), increased circulating EPC with improved colony forming and migratory capacity, enhanced incorporation into tube-like structures, and augmented endothelial nitric oxide synthase expression in EPC comparable to that of the younger group. EPC senescence was attenuated, whereas telomerase activity was increased after GH treatment. Treatment of aged mice with GH (7 days) or IGF-1 increased IGF-1 and EPC levels and improved EPC function, whereas a two day GH treatment did not alter IGF-1 or EPC levels. Ex vivo treatment of EPC from elderly individuals with IGF-1 improved function and attenuated cellular senescence. IGF-1 stimulated EPC differentiation, migratory capacity and the ability to incorporate into forming vascular networks in vitro via the IGF-1 receptor. IGF-1 increased telomerase activity, endothelial nitric oxide synthase expression, phosphorylation and activity in EPC in a phosphoinositide-3-kinase/Akt dependent manner. Small interference RNA-mediated knockdown of endothelial nitric oxide synthase in EPC abolished the IGF-1 effects. Growth hormone-mediated increase in IGF-1 reverses age-related EPC dysfunction and may be a novel therapeutic strategy against vascular disorders with impairment of EPC.
authors.affiliation: Universität Würzburg, Medizinische Klinik I (Kardiologie), Würzburg, Germany. Thum_T@klinik.uni-wuerzburg.de
authors.forename: Thomas
authors.initials: T
authors.lastname: Thum
authors.forename: Sarah
authors.initials: S
authors.lastname: Hoeber
authors.forename: Sabrina
authors.initials: S
authors.lastname: Froese
authors.forename: Ivonne
authors.initials: I
authors.lastname: Klink
authors.forename: Dirk O
authors.initials: DO
authors.lastname: Stichtenoth
authors.forename: Paolo
authors.initials: P
authors.lastname: Galuppo
authors.forename: Marten
authors.initials: M
authors.lastname: Jakob
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Tsikas
authors.forename: Stefan D
authors.initials: SD
authors.lastname: Anker
authors.forename: Philip A
authors.initials: PA
authors.lastname: Poole-Wilson
authors.forename: Jürgen
authors.initials: J
authors.lastname: Borlak
authors.forename: Georg
authors.initials: G
authors.lastname: Ertl
authors.forename: Johann
authors.initials: J
authors.lastname: Bauersachs
mesh_terms: D000328:Adult; D000368:Aged; D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D003114:Colony-Forming Units Assay; D004730:Endothelium, Vascular / Q000166:cytology*; D004790:Enzyme Induction / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D013006:Growth Hormone / Q000494:pharmacology / Q000502:physiology*; D019382:Human Growth Hormone / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000032:analysis / Q000172:deficiency / Q000502:physiology*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects*; D051379:Mice; D008875:Middle Aged; D052247:Nitric Oxide Synthase Type II / Q000502:physiology; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D019098:Telomerase / Q000096:biosynthesis / Q000235:genetics; D001616:beta-Galactosidase / Q000032:analysis; D014841:von Willebrand Factor / Q000096:biosynthesis / Q000235:genetics
chemical_list: D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D014841:von Willebrand Factor; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; C496314:NOS3 protein, human; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1; C494918:AKT1 protein, human; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; C509186:TERT protein, human; D019098:Telomerase; C509187:Tert protein, mouse; D001616:beta-Galactosidase