title: Intracellular oxidant activity, antioxidant enzyme defense system, and cell senescence in fibroblasts with trisomy 21.
abstract: Down's syndrome (DS) is characterized by a complex phenotype associated with chronic oxidative stress and mitochondrial dysfunction. Overexpression of genes on chromosome-21 is thought to underlie the pathogenesis of the major phenotypic features of DS, such as premature aging. Using cultured fibroblasts with trisomy 21 (T21F), this study aimed to ascertain whether an imbalance exists in activities, mRNA, and protein expression of the antioxidant enzymes SOD1, SOD2, glutathione-peroxidase, and catalase during the cell replication process in vitro. T21F had high SOD1 expression and activity which led to an interenzymatic imbalance in the antioxidant defense system, accentuated with replicative senescence. Intracellular ROS production and oxidized protein levels were significantly higher in T21F compared with control cells; furthermore, a significant decline in intracellular ATP content was detected in T21F. Cell senescence was found to appear prematurely in DS cells as shown by SA-β-Gal assay and p21 assessment, though not apoptosis, as neither p53 nor the proapoptotic proteins cytochrome c and caspase 9 were altered in T21F. These novel findings would point to a deleterious role of oxidatively modified molecules in early cell senescence of T21F, thereby linking replicative and stress-induced senescence in cultured cells to premature aging in DS.
authors: Center for Biomedical Network Research on Rare Diseases (CIBERER), 08028 Barcelona, Spain ; Biochemistry and Molecular Biology Research Center for Nanomedicine, Vall d'Hebron Research Institute, 08035 Barcelona, Spain.
authors: Víctor
authors: V
authors: Rodríguez-Sureda
authors: Biochemistry and Molecular Biology Research Center for Nanomedicine, Vall d'Hebron Research Institute, 08035 Barcelona, Spain.
authors: Ángel
authors: Á
authors: Vilches
authors: Biochemistry and Molecular Biology Research Center for Nanomedicine, Vall d'Hebron Research Institute, 08035 Barcelona, Spain ; Maternal and Child Health and Development Network II (SAMID II), Institute of Health Carlos III, 28029 Madrid, Spain.
authors: Olga
authors: O
authors: Sánchez
authors: Center for Biomedical Network Research on Rare Diseases (CIBERER), 08028 Barcelona, Spain ; Paediatric Endocrine Service, Vall d'Hebron University Hospital, 08035 Barcelona, Spain.
authors: Laura
authors: L
authors: Audí
authors: Center for Biomedical Network Research on Rare Diseases (CIBERER), 08028 Barcelona, Spain ; Biochemistry and Molecular Biology Research Center for Nanomedicine, Vall d'Hebron Research Institute, 08035 Barcelona, Spain.
authors: Carmen
authors: C
authors: Domínguez
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000975:Antioxidants / Q000378:metabolism*; D053453:Caspase 9 / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D016922:Cellular Senescence; D045304:Cytochromes c / Q000378:metabolism; D004314:Down Syndrome / Q000378:metabolism / Q000473:pathology; D005333:Fetus / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D014314:Trisomy / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000099156:Superoxide Dismutase 2
chemical_list: D000255:Adenosine Triphosphate; D000975:Antioxidants; D053453:Caspase 9; D002374:Catalase; D045304:Cytochromes c; D005979:Glutathione Peroxidase; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D016159:Tumor Suppressor Protein p53; D000099156:Superoxide Dismutase 2; C000606290:SOD1 protein, human