title: Differential Regulation of the Extracellular Cysteine/Cystine Redox State (EhCySS) by Lung Fibroblasts from Young and Old Mice.
abstract: Aging is associated with progressive oxidation of plasma cysteine (Cys)/cystine (CySS) redox state, expressed as EhCySS. Cultured cells condition their media to reproduce physiological EhCySS, but it is unknown whether aged cells produce a more oxidized extracellular environment reflective of that seen in vivo. In the current study, we isolated primary lung fibroblasts from young and old female mice and measured the media EhCySS before and after challenge with Cys or CySS. We also measured expression of genes related to redox regulation and fibroblast function. These studies revealed that old fibroblasts produced a more oxidizing extracellular EhCySS than young fibroblasts and that old fibroblasts had a decreased capacity to recover from an oxidative challenge due to a slower rate of reduction of CySS to Cys. These defects were associated with 10-fold lower expression of the Slc7a11 subunit of the xCT cystine-glutamate transporter. Extracellular superoxide dismutase (Sod3) was the only antioxidant or thiol-disulfide regulating enzyme among 36 examined that was downregulated in old fibroblasts by more than 2-fold, but there were numerous changes in extracellular matrix components. Thus, aging fibroblasts not only contribute to remodeling of the extracellular matrix but also have a profound effect on the extracellular redox environment.
authors.affiliation: Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Louisville School of Medicine, Louisville, KY, USA; Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA.
authors.forename: Walter H
authors.identifier: 0000-0002-4381-1087
authors.initials: WH
authors.lastname: Watson
authors.affiliation: Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Louisville School of Medicine, Louisville, KY, USA.
authors.forename: Tom J
authors.identifier: 0000-0002-0902-6229
authors.initials: TJ
authors.lastname: Burke
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY, USA; Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Louisville School of Medicine, Louisville, KY, USA.
authors.forename: Igor N
authors.identifier: 0000-0003-3976-3884
authors.initials: IN
authors.lastname: Zelko
authors.affiliation: Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Louisville School of Medicine, Louisville, KY, USA; Robley Rex Veterans Affairs Medical Center, Louisville, KY, USA.
authors.forename: Edilson
authors.identifier: 0000-0002-0136-3562
authors.initials: E
authors.lastname: Torres-González
authors.affiliation: Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Louisville School of Medicine, Louisville, KY, USA.
authors.forename: Jeffrey D
authors.identifier: 0000-0003-0511-1992
authors.initials: JD
authors.lastname: Ritzenthaler
authors.affiliation: Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA; Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Louisville School of Medicine, Louisville, KY, USA; Robley Rex Veterans Affairs Medical Center, Louisville, KY, USA.
authors.forename: Jesse
authors.initials: J
authors.lastname: Roman
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000375:Aging; D000818:Animals; D002478:Cells, Cultured; D003545:Cysteine / Q000737:chemistry* / Q000378:metabolism; D003553:Cystine / Q000737:chemistry* / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000166:cytology*; D051379:Mice; D010084:Oxidation-Reduction; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: C558396:Acta2 protein, mouse; D000199:Actins; D005353:Fibronectins; D016212:Transforming Growth Factor beta; D003553:Cystine; D013482:Superoxide Dismutase; D003545:Cysteine