title: Reprogramming ageing and longevity genes restores paracrine angiogenic properties of early outgrowth cells.
abstract: Impaired tissue vascularization is a major determinant of cardiovascular disease (CVD) in the elderly. Accumulation of reactive oxygen species (ROS) may interfere with vascular repair, but the underlying mechanisms remain unknown. Early outgrowth cells (EOCs) play an important role in endothelial repair. We investigated whether key lifespan genes involved in ROS, i.e. the mitochondrial adaptor p66(Shc) and the AP-1 transcription factor JunD, contribute to age-related EOCs dysfunction in humans.
  
  
  
  Early outgrowth cells were isolated and cultured from peripheral blood mononuclear cells of young and old healthy volunteers. Early outgrowth cells isolated from aged individuals displayed p66(Shc) gene up-regulation and reduced JunD expression. Deregulation of p66(Shc) and JunD in aged EOCs led to up-regulation of NADPH oxidase, reduced expression of manganese superoxide dismutase (MnSOD) and increased O2 (-) generation. This was associated with an impairment of EOCs-induced migration of mature endothelial cells. Secretome profiling revealed that angiogenic chemokines such as stromal-derived factor-1 and monocyte chemoattractant protein-1 were deregulated in conditioned medium collected from aged EOCs. Interestingly, p66(Shc) silencing or JunD overexpression blunted age-related O2 (-) production via the NADPH/MnSOD axis, and restored paracrine angiogenic potential of aged EOCs.
  
  
  
  Reprogramming ageing and longevity genes preserves EOCs functionality by affecting their paracrine properties. These findings set the basis for novel therapeutic strategies to improve for vascular repair after injury and in CVD in the elderly.
authors.affiliation: Center for Molecular Cardiology, University of Zurich, Zürich, Switzerland Cardiology Unit, Department of Medicine, Karolinska University Hospital, Solna, Stockholm, Sweden.
authors.forename: Francesco
authors.initials: F
authors.lastname: Paneni
authors.affiliation: Center for Molecular Cardiology, University of Zurich, Zürich, Switzerland Cardiology Unit, Department of Medicine, Karolinska University Hospital, Solna, Stockholm, Sweden.
authors.forename: Sarah
authors.initials: S
authors.lastname: Costantino
authors.affiliation: Department of Cardiology, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, Berlin 12203, Germany.
authors.forename: Nicolle
authors.initials: N
authors.lastname: Kränkel
authors.affiliation: Cardiology Unit, Department of Medicine, Karolinska University Hospital, Solna, Stockholm, Sweden.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cosentino
authors.affiliation: Center for Molecular Cardiology, University of Zurich, Zürich, Switzerland Department of Cardiology, University Heart Center, University Hospital Zurich, Zürich 8091, Switzerland thomas.luescher@usz.ch.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Lüscher
mesh_terms: D000375:Aging; D018932:Chemokine CCL2; D042783:Endothelial Cells; D006801:Humans; D007963:Leukocytes, Mononuclear; D008136:Longevity
chemical_list: D018932:Chemokine CCL2
keywords: Ageing; Angiogenesis; Cardiovascular disease; Endothelial progenitor cells; Regenerative medicine; Vascular repair