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Akt downregulation by flavin oxidase–induced ROS generation mediates dose-dependent endothelial cell damage elicited by natural antioxidants

Pasciu, Valeria and Posadino, Anna Maria and Cossu, Annalisa and Sanna, Bastiano and Tadolini, Bruna and Gaspa, Leonardo and Marchisio, Andrea and Dessole, Salvatore and Capobianco, Giampiero and Pintus, Gianfranco (2010) Akt downregulation by flavin oxidase–induced ROS generation mediates dose-dependent endothelial cell damage elicited by natural antioxidants. Toxicological Sciences, Vol. 114 (1), p. 101-112. eISSN 1096-0929. Article.

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DOI: 10.1093/toxsci/kfp301

Abstract

High intake of natural antioxidants (NA) from plant-derived foods and beverages is thought to provide cardiovascular benefits. The endothelium plays a pivotal role in cardiovascular homeostasis, and for this reason, the molecular events resulting from NA actions on endothelial cells (ECs) are actively investigated. Here, we show the direct impact of two NA, coumaric acid and resveratrol, on intracellular reactive oxygen species levels, protein carbonylation, and cell physiology in human ECs. While at lower doses, both NA promoted antioxidant effects, at moderately high doses, NA elicited a dose-dependent pro-oxidant effect, which was followed by apoptosis, cell damage, and phospho-Akt downregulation. NA-induced pro-oxidant effects were counteracted by N-acetyl cysteine and diphenyleneiodonium (DPI), suggesting a role for flavin oxidases in NA-induced toxicity. DPI also prevented NA-induced phospho-Akt downregulation indicating that Akt can work downstream of flavin oxidases in mediating cellular responses to NA. Stimulation of phospho-Akt by insulin dramatically counteracted NA-induced cell death, an effect abolished by Akt inhibition further suggesting that mechanistically Akt regulates cell survival in response to NA-induced stress. Although further studies are required to better characterize the molecular mechanism of NA-induced cell toxicity, our study is the first to show in a human vascular model that moderately high doses of NA can induce cell damage mediated by flavoproteins and the Akt pathway.

Item Type:Article
ID Code:3933
Status:Published
Refereed:Yes
Uncontrolled Keywords:ROS, natural antioxidants, endothelial cells, antioxidant and pro-oxidant effect, cell damage, Akt
Subjects:Area 06 - Scienze mediche > MED/40 Ginecologia e ostetricia
Area 05 - Scienze biologiche > BIO/10 Biochimica
Divisions:001 Università di Sassari > 01 Dipartimenti > Scienze biomediche
002 Altri enti e centri di ricerca del Nord Sardegna > National laboratory of the national institute of biostructures and biosystems, Osilo
001 Università di Sassari > 01 Dipartimenti > Neuroscienze, scienze materno infantili
Publisher:Oxford University Press
eISSN:1096-0929
Copyright Holders:© The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology
Deposited On:24 May 2010 18:52

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