title: Prominent role of exopeptidase DPP III in estrogen-mediated protection against hyperoxia in vivo.
abstract: A number of age-related diseases have a low incidence in females, which is attributed to a protective effect of sex hormones. For instance, the female sex hormone estrogen (E2) has a well established cytoprotective effect against oxidative stress, which strongly contributes to ageing. However, the mechanism by which E2 exerts its protective activity remains elusive. In this study we address the question whether the E2-induced protective effect against hyperoxia is mediated by the Nrf-2/Keap-1 signaling pathway. In particular, we investigate the E2-induced expression and cellular distribution of DPP III monozinc exopeptidase, a member of the Nrf-2/Keap-1 pathway, upon hyperoxia treatment. We find that DPP III accumulates in the nucleus in response to hyperoxia. Further, we show that combined induction of hyperoxia and E2 administration have an additive effect on the nuclear accumulation of DPP III. The level of nuclear accumulation of DPP III is comparable to nuclear accumulation of Nrf-2 in healthy female mice exposed to hyperoxia. In ovariectomized females exposed to hyperoxia, supplementation of E2 induced upregulation of DPP III, Ho-1, Sirt-1 and downregulation of Ppar-γ. While other cytoprotective mechanisms cannot be excluded, these findings demonstrate a prominent role of DPP III, along with Sirt-1, in the E2-mediated protection against hyperoxia.
authors.affiliation: Division of Molecular Medicine, Ruđer Bošković Institute, Zagreb, Croatia. Electronic address: ssoboc@irb.hr.
authors.forename: Sandra
authors.initials: S
authors.lastname: Sobočanec
authors.affiliation: Division of Molecular Biology, Ruđer Bošković Institute, Zagreb, Croatia.
authors.forename: Vedrana
authors.initials: V
authors.lastname: Filić
authors.affiliation: Division of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Zagreb, Croatia.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Matovina
authors.affiliation: Division of Molecular Biology, Ruđer Bošković Institute, Zagreb, Croatia.
authors.forename: Dragomira
authors.initials: D
authors.lastname: Majhen
authors.affiliation: Division of Molecular Medicine, Ruđer Bošković Institute, Zagreb, Croatia.
authors.forename: Željka Mačak
authors.initials: ŽM
authors.lastname: Šafranko
authors.affiliation: Division of Molecular Medicine, Ruđer Bošković Institute, Zagreb, Croatia.
authors.forename: Marijana Popović
authors.initials: MP
authors.lastname: Hadžija
authors.affiliation: Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia.
authors.forename: Željka
authors.initials: Ž
authors.lastname: Krsnik
authors.affiliation: Department of Veterinary Pathology, Faculty of Veterinary Medicine, University of Zagreb, Zagreb, Croatia.
authors.forename: Andrea Gudan
authors.initials: AG
authors.lastname: Kurilj
authors.affiliation: Division of Molecular Medicine, Ruđer Bošković Institute, Zagreb, Croatia.
authors.forename: Ana
authors.initials: A
authors.lastname: Šarić
authors.affiliation: Division of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Zagreb, Croatia.
authors.forename: Marija
authors.initials: M
authors.lastname: Abramić
authors.affiliation: Division of Molecular Medicine, Ruđer Bošković Institute, Zagreb, Croatia.
authors.forename: Tihomir
authors.initials: T
authors.lastname: Balog
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D001835:Body Weight; D004249:DNA Damage; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004967:Estrogens / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D018496:Hyperoxia / Q000235:genetics / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000378:metabolism; D051379:Mice; D008808:Mice, Inbred CBA; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D010052:Ovariectomy; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D004967:Estrogens; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D047495:PPAR gamma; D051547:Heme Oxygenase-1; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D056564:Sirtuin 1; D005978:Glutathione
keywords: DPP III; Estradiol; Ho-1; Hyperoxia; Mice; Nrf-2; Oxidative stress; Ppar-γ; Sirt-1