title: Free radical production, antioxidant capacity, and oxidative stress response signatures in fibroblasts from Lewis dwarf rats: effects of life span-extending peripubertal GH treatment.
abstract: The discovery that in invertebrates, disruption of the insulin/insulin-like growth factor (IGF)-1 pathway extends life span and increases resistance to oxidative injury led to the hypothesis that IGF-1 signaling may play a role in regulating cellular reactive oxygen species production, oxidative stress resistance, and consequentially, organismal life span in mammals. However, previous studies testing this hypothesis in rodent models of IGF-1 deficiency yielded controversial results. The Lewis dwarf rat is a useful model of human growth hormone (GH)/IGF-1 deficiency as it mimics many of the pathophysiological alterations present in human GH/IGF-1-deficient patients as well as elderly individuals. Peripubertal treatment of Lewis dwarf rats with GH results in a significant extension of life span. The present study was designed to test the role of the GH/IGF-1 axis in regulating cellular oxidative stress and oxidative stress resistance, utilizing primary fibroblasts derived from control rats, Lewis dwarf rats and GH-replete dwarf rats. Measurements of cellular dihydroethidium and C-H(2)DCFDA fluorescence showed that cellular O(2)(·-) and peroxide production were similar in each group. Fibroblasts from control and Lewis dwarf rats exhibited similar antioxidant capacities and comparable sensitivity to H(2)O(2), rotenone, high glucose, tunicamycin, thapsigargin, paraquat, and mitomycin, which cause apoptosis through increasing oxidative stress, mitochondrial damage, ATP depletion, and/or by damaging DNA, lipids and proteins. Fibroblasts from GH-replete rats exhibited significantly increased antioxidant capacities and superior resistance to H(2)O(2), rotenone and bacterial lipopolysaccharide-induced cell death compared with cells from Lewis dwarf rats, whereas their sensitivity to the other stressors investigated was not statistically different. Thus, low circulating IGF-1 levels present in vivo in Lewis dwarf rats do not elicit long-lasting alterations in cellular reactive oxygen species generation and oxidative stress resistance, whereas life span-extending peripubertal GH treatment resulted in increased antioxidant capacity and increased resistance to cellular injury caused by some, but not all, oxidative stressors.
authors.affiliation: Reynolds Oklahoma Center on Aging, Donald W Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Ungvari
authors.forename: Danuta
authors.initials: D
authors.lastname: Sosnowska
authors.forename: Andrej
authors.initials: A
authors.lastname: Podlutsky
authors.forename: Peter
authors.initials: P
authors.lastname: Koncz
authors.forename: William E
authors.initials: WE
authors.lastname: Sonntag
authors.forename: Anna
authors.initials: A
authors.lastname: Csiszar
mesh_terms: D000818:Animals; D005260:Female; D005347:Fibroblasts / Q000502:physiology; D005609:Free Radicals / Q000378:metabolism*; D013006:Growth Hormone / Q000494:pharmacology*; D008136:Longevity / Q000187:drug effects*; D008297:Male; D018384:Oxidative Stress / Q000502:physiology*; D051381:Rats; D011917:Rats, Inbred Lew; D011922:Rats, Mutant Strains; D017382:Reactive Oxygen Species / Q000097:blood; D013002:Somatomedins / Q000494:pharmacology
chemical_list: D005609:Free Radicals; D017382:Reactive Oxygen Species; D013002:Somatomedins; D013006:Growth Hormone