title: Thioredoxin-1/peroxiredoxin-1 as sensors of oxidative stress mediated by NADPH oxidase activity in atherosclerosis.
abstract: To assess the potential association between TRX-1/PRX-1 and NADPH oxidase (Nox) activity in vivo and in vitro, TRX-1/PRX-1 levels were assessed by ELISA in 84 asymptomatic subjects with known phagocytic NADPH oxidase activity and carotid intima-media thickness (IMT). We found a positive correlation between TRX-1/PRX-1 and NADPH oxidase-dependent superoxide production (r=0.48 and 0.47; p<0.001 for both) and IMT (r=0.31 and 0.36; p<0.01 for both) adjusted by age and sex. Moreover, asymptomatic subjects with plaques have higher PRX-1 and TRX plasma levels (p<0.01 for both). These data were confirmed in a second study in which patients with carotid atherosclerosis showed higher PRX-1 and TRX plasma levels than healthy subjects (p<0.001 for both). In human atherosclerotic plaques, the NADPH oxidase subunit p22phox colocalized with TRX-1/PRX-1 in macrophages (immunohistochemistry). In monocytes and macrophages, phorbol 12-myristate 13-acetate (PMA) induced NADPH activation and TRX-1/PRX-1 release to the extracellular medium, with a concomitant decrease in their intracellular levels, which was reversed by the NADPH inhibitor apocynin (Western blot). In loss-of-function experiments, genetic silencing of the NADPH oxidase subunit Nox2 blocked PMA-induced intracellular TRX-1/PRX-1 downregulation in macrophages. Furthermore, the PMA-induced release of TRX-1/PRX-1 involves the modulation of their redox status and exosome-like vesicles. TRX-1/PRX-1 levels are associated with NADPH oxidase-activity in vivo and in vitro. These data could suggest a coordinated antioxidant response to oxidative stress in atherothrombosis.
authors.affiliation: Vascular Research Laboratory, ISS-Fundación Jimenez Diaz, Autonoma University, 28040 Madrid, Spain; Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Julio
authors.initials: J
authors.lastname: Madrigal-Matute
authors.affiliation: Vascular Research Laboratory, ISS-Fundación Jimenez Diaz, Autonoma University, 28040 Madrid, Spain.
authors.forename: Carlos-Ernesto
authors.initials: CE
authors.lastname: Fernandez-Garcia
authors.affiliation: Vascular Research Laboratory, ISS-Fundación Jimenez Diaz, Autonoma University, 28040 Madrid, Spain.
authors.forename: Luis Miguel
authors.initials: LM
authors.lastname: Blanco-Colio
authors.affiliation: Vascular Research Laboratory, ISS-Fundación Jimenez Diaz, Autonoma University, 28040 Madrid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Burillo
authors.affiliation: Division of Cardiovascular Sciences, Center for Applied Medical Research University of Navarra, Pamplona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Fortuño
authors.affiliation: Vascular Research Laboratory, ISS-Fundación Jimenez Diaz, Autonoma University, 28040 Madrid, Spain.
authors.forename: Roxana
authors.initials: R
authors.lastname: Martinez-Pinna
authors.affiliation: Vascular Research Laboratory, ISS-Fundación Jimenez Diaz, Autonoma University, 28040 Madrid, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Llamas-Granda
authors.affiliation: Department of Internal Medicine, University Clinic, University of Navarra, Pamplona, Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: Beloqui
authors.affiliation: Vascular Research Laboratory, ISS-Fundación Jimenez Diaz, Autonoma University, 28040 Madrid, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Madrid, Spain.
authors.forename: Jesus
authors.initials: J
authors.lastname: Egido
authors.affiliation: Division of Cardiovascular Sciences, Center for Applied Medical Research University of Navarra, Pamplona, Spain; Department of Biochemistry and Genetics, University of Navarra, Pamplona, Spain.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Zalba
authors.affiliation: Vascular Research Laboratory, ISS-Fundación Jimenez Diaz, Autonoma University, 28040 Madrid, Spain. Electronic address: jlmartin@fjd.es.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Martin-Ventura
mesh_terms: D000368:Aged; D058070:Asymptomatic Diseases; D015415:Biomarkers / Q000097:blood; D002340:Carotid Artery Diseases / Q000097:blood / Q000000981:diagnostic imaging / Q000201:enzymology*; D059168:Carotid Intima-Media Thickness; D016022:Case-Control Studies; D002460:Cell Line; D005260:Female; D006801:Humans; D008264:Macrophages / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D019255:NADPH Oxidases / Q000378:metabolism*; D018384:Oxidative Stress; D054464:Peroxiredoxins / Q000097:blood*; D021381:Protein Transport; D013879:Thioredoxins / Q000097:blood*
chemical_list: D015415:Biomarkers; C491203:TXN protein, human; D013879:Thioredoxins; D054464:Peroxiredoxins; D019255:NADPH Oxidases; C086986:CYBA protein, human
keywords: Atherosclerosis; Free radicals; NADPH oxidase; Oxidative stress; Peroxiredoxin; Thioredoxin