title: Microparticles from patients with metabolic syndrome induce vascular hypo-reactivity via Fas/Fas-ligand pathway in mice.
abstract: Microparticles are membrane vesicles with pro-inflammatory properties. Circulating levels of microparticles have previously been found to be elevated in patients with metabolic syndrome (MetS). The present study aimed to evaluate the effects of in vivo treatment with microparticles, from patients with MetS and from healthy subjects (HS), on ex vivo vascular function in mice. Microparticles isolated from MetS patients or HS, or a vehicle were intravenously injected into mice, following which vascular reactivity in response to vasoconstrictor agonists was assessed by myography with respect to cyclo-oxygenase pathway, oxidative and nitrosative stress. Injection of microparticles from MetS patients into mice induced vascular hypo-reactivity in response to serotonin. Hypo-reactivity was associated with up-regulation of inducible NO-synthase and increased production of NO, and was reversed by the NO-synthase inhibitor (N(G)-nitro-L-arginine). The selective COX-2 inhibitor (NS398) reduced the contractile effect of serotonin in aortas from mice treated with vehicle or HS microparticles; however, this was not observed within mice treated with MetS microparticles, probably due to the ability of MetS microparticles to enhance prostacyclin. MetS microparticle-mediated vascular dysfunction was associated with increased reactive oxygen species (ROS) and enhanced expression of the NADPH oxidase subunits. Neutralization of the pro-inflammatory pathway Fas/FasL completely prevented vascular hypo-reactivity and the ability of MetS microparticles to enhance both inducible NO-synthase and monocyte chemoattractant protein-1 (MCP-1). Our data provide evidence that microparticles from MetS patients induce ex vivo vascular dysfunction by increasing both ROS and NO release and by altering cyclo-oxygenase metabolites and MCP-1 through the Fas/FasL pathway.
authors: INSERM, U694, Angers, France.
authors: Abdelali
authors: A
authors: Agouni
authors: Pierre-Henri
authors: PH
authors: Ducluzeau
authors: Tarek
authors: T
authors: Benameur
authors: Sébastien
authors: S
authors: Faure
authors: Martina
authors: M
authors: Sladkova
authors: Lucie
authors: L
authors: Duluc
authors: Georges
authors: G
authors: Leftheriotis
authors: Olga
authors: O
authors: Pechanova
authors: Mirela
authors: M
authors: Delibegovic
authors: Maria Carmen
authors: MC
authors: Martinez
authors: Ramaroson
authors: R
authors: Andriantsitohaina
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology* / Q000378:metabolism*; D055252:Cell-Derived Microparticles / Q000378:metabolism*; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D053222:Fas Ligand Protein / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008297:Male; D024821:Metabolic Syndrome / Q000473:pathology*; D051379:Mice; D008875:Middle Aged; D019255:NADPH Oxidases / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D019014:fas Receptor / Q000378:metabolism*
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D053222:Fas Ligand Protein; C491899:Fas protein, mouse; D017382:Reactive Oxygen Species; D019014:fas Receptor; D009569:Nitric Oxide; D051546:Cyclooxygenase 2; D019255:NADPH Oxidases