title: Endothelial progenitor cell function, apoptosis, and telomere length in overweight/obese humans.
abstract: Excess adiposity is associated with increased cardiovascular morbidity and mortality. Endothelial progenitor cells (EPCs) play an important role in vascular repair. We tested the hypothesis that increased adiposity is associated with EPC dysfunction, characterized by diminished capacity to release angiogenic cytokines, increased apoptotic susceptibility, reduced cell migration, and shorter telomere length. A total of 67 middle-aged and older adults (42-67 years) were studied: 25 normal weight (normal weight; BMI: 18.5-24.9 kg/m(2)) and 42 overweight/obese (overweight/obese; BMI: 25.0-34.9 kg/m(2)). Cells with phenotypic EPC characteristics were isolated from peripheral blood. EPC release of vascular endothelial growth factor (VEGF) and granulocyte colony-stimulating factor (G-CSF) was determined in the absence and presence of phytohemagglutinin (10 microg/ml). Intracellular active caspase-3 and cytochrome c concentrations were determined by immunoassay. Migratory activity of EPCs in response to VEGF (2 ng/ml) and stromal cell-derived factor-1alpha (SDF-1alpha; 10 ng/ml) was determined by Boyden chamber. Telomere length was assessed by Southern hybridization. Phytohemagglutinin-stimulated release of VEGF (90.6 +/- 7.6 vs. 127.2 +/- 11.6 pg/ml) and G-CSF (896.1 +/- 77.4 vs. 1,176.3 +/- 126.3 pg/ml) was ~25% lower (P < 0.05) in EPCs from overweight/obese vs. normal weight subjects. Staurosporine induced a ~30% greater (P < 0.05) increase in active caspase-3 in EPCs from overweight/obese (2.8 +/- 0.2 ng/ml) compared with normal weight (2.2 +/- 0.2) subjects. There were no significant differences in EPC migration to either VEGF or SDF-1alpha. Telomere length did not differ between groups. These results indicate that increased adiposity adversely affects the ability of EPCs to release proangiogenic cytokines and resist apoptosis, potentially compromising their reparative potential.
authors.affiliation: Integrative Vascular Biology Laboratory, Department of Integrative Physiology, University of Colorado, Boulder, Colorado, USA.
authors.forename: Owen J
authors.initials: OJ
authors.lastname: MacEneaney
authors.forename: Erich J
authors.initials: EJ
authors.lastname: Kushner
authors.forename: Christian M
authors.initials: CM
authors.lastname: Westby
authors.forename: Jennifer N
authors.initials: JN
authors.lastname: Cech
authors.forename: Jared J
authors.initials: JJ
authors.lastname: Greiner
authors.forename: Brian L
authors.initials: BL
authors.lastname: Stauffer
authors.forename: Christopher A
authors.initials: CA
authors.lastname: DeSouza
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism*; D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D042783:Endothelial Cells / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D008875:Middle Aged; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology*; D037121:Plant Lectins / Q000494:pharmacology; D019311:Staurosporine / Q000494:pharmacology; D013234:Stem Cells / Q000502:physiology*; D016615:Telomere; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D054377:Chemokine CXCL12; D016207:Cytokines; D004791:Enzyme Inhibitors; D037121:Plant Lectins; D042461:Vascular Endothelial Growth Factor A; D016179:Granulocyte Colony-Stimulating Factor; D045304:Cytochromes c; D053148:Caspase 3; D019311:Staurosporine