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Phosphatidylinositol 3-Kinase and Xanthine Oxidase Regulate Nitric Oxide and Reactive Oxygen Species Productions by Apoptotic Lymphocyte Microparticles in Endothelial Cells¹

H. Ahmed Mostefai^2,*, Abdelali Agouni^2,*, Nunzia Carusio^*, M. Letizia Mastronardi^*, Christophe Heymes, Daniel Henrion^*, Ramaroson Andriantsitohaina^* and M. Carmen Martinez^3,*

^* Centre National de la Recherche Scientifique Unité Mixte de Recherche 6214, Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 771, and Université d’Angers, Angers, France; and INSERM, Unité 689, Paris, France

Microparticles (MPs) are membrane vesicles released during cell activation and apoptosis. We have previously shown that MPs from apoptotic T cells induce endothelial dysfunction, but the mechanisms implicated are not completely elucidated. In this study, we dissect the pathways involved in endothelial cells with respect to both NO and reactive oxygen species (ROS). Incubation of endothelial cells with MPs decreased NO production that was associated with overexpression and phosphorylation of endothelial NO synthase (eNOS). Also, MPs enhanced expression of caveolin-1 and decreased its phosphorylation. Microparticles enhanced ROS by a mechanism sensitive to xanthine oxidase and P-IB inhibitors. PI3K inhibition reduced the effects of MPs on eNOS, but not on caveolin-1, whereas it enhanced the effects of MPs on ROS production. Microparticles stimulated ERK1/2 phosphorylation via a PI3K-depedent mechanism. Inhibition of MEK reversed eNOS phosphorylation but had no effect on ROS production induced by MPs. In vivo injection of MPs in mice impaired endothelial function. In summary, MPs activate pathways related to NO and ROS productions through PI3K, xanthine oxidase, and NF-B pathways. These data underscore the pleiotropic effects of MPs on NO and ROS, leading to an increase oxidative stress that may account for the deleterious effects of MPs on endothelial function.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by grants from Fonds Européen pour le Développement Régional (R.A. 8891), Fondation pour la Recherche Médicale (R.A. INE20050303433 and MCM INE20060306500), Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale Unité et Université d’Angers. H.A.M. and A.A. are recipients of a doctoral fellowship from Conseil Régional du Pays de la Loire and French Education Ministry, respectively.

² H.A.M. and A.A. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. M. Carmen Martinez, Biologie Neuro-Vasculaire Intégrée, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 6214, Faculté de Médecine, Institut National de la Santé et de la Recherche Médicale Unité 771, Rue Haute de Reculée, 49045 Angers, France. E-mail address: carmen.martinez{at}univ-angers.fr

⁴ Abbreviation used in this paper: MP, microparticle; ROS, reactive oxygen species; eNOS, endothelial NO synthase; EPR, electronic paramagnetic resonance; DETC, diethyldithiocarbamate; DHE, dihydroethidine; siRNA, small-interfering RNA; MnTMPyP, manganese(III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride; O₂, superoxide anion; L-NA, nitro-L-arginine.

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