Thioredoxin-1/peroxiredoxin-1 as sensors of oxidative stress mediated by NADPH oxidase activity in atherosclerosis

• Published in: Free radical biology & medicine Vol. 86; pp. 352 - 361
• Main Authors: Madrigal-Matute, Julio, Fernandez-Garcia, Carlos-Ernesto, Blanco-Colio, Luis Miguel, Burillo, Elena, Fortuño, Ana, Martinez-Pinna, Roxana, Llamas-Granda, Patricia, Beloqui, Oscar, Egido, Jesus, Zalba, Guillermo, Martin-Ventura, José Luis
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2015
• Subjects: Aged; Asymptomatic Diseases; Atherosclerosis; Biomarkers - blood; Carotid Artery Diseases - blood; Carotid Artery Diseases - diagnostic imaging; Carotid Artery Diseases - enzymology; Carotid Intima-Media Thickness; Case-Control Studies; Cell Line; Female; Free radicals; Humans; Macrophages - enzymology; Male; Middle Aged; NADPH oxidase; NADPH Oxidases - metabolism; Oxidative Stress; Peroxiredoxin; Peroxiredoxins - blood; Protein Transport; Thioredoxin; Thioredoxins - blood; Peroxiredoxin; Oxidative stress; Free radicals; Thioredoxin; NADPH oxidase; Atherosclerosis
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2015.06.001

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. [Display omitted] •TRX-1 and PRDX-1 circulating levels are associated with atherosclerosis severity.•Human primary monocytes show a positive correlation between Nox activity and circulating levels of TRX-1 and PRDX-1.•The catalytic isoform Nox2 plays a key role in the oxidative-induced release of TRX-1 and PRDX-1 to the extracellular milieu.•TRX-1 and PRDX-1 are released from the cells through exosomes, among other mechanisms.