Microparticles from Patients with Metabolic Syndrome Induce Vascular Hypo-Reactivity via Fas/Fas-Ligand Pathway in Mice
Microparticles from Patients with Metabolic Syndrome Induce Vascular Hypo-Reactivity via Fas/Fas-Ligand Pathway in Mice
复制标题
DOI：
10.1371/journal.pone.0027809
复制
发表时间：
2011-11-15
期刊：
影响因子：
3.7
通讯作者：
Andriantsitohaina, Ramaroson
中科院分区：
文献类型：
--
作者：
Agouni, Abdelali;Ducluzeau, Pierre-Henri;Andriantsitohaina, Ramaroson
微粒是具有促炎特性的膜囊泡。先前已发现微粒的循环水平在代谢综合征（MetS）患者中升高。本研究的目的是评估体内治疗与微粒的影响，从患者MetS和健康受试者（HS），离体血管功能的小鼠。将从MetS患者或HS分离的微粒或载体静脉内注射到小鼠中，随后通过关于环加氧酶途径、氧化和亚硝化应激的肌造影术评估对血管收缩剂激动剂的血管反应性。将来自MetS患者的微粒注射到小鼠中诱导血管对5-羟色胺的低反应性。低反应性与诱导型NO合酶的上调和NO的产生增加有关，并且被NO合酶抑制剂（N（G）-硝基-L-精氨酸）逆转。选择性考克斯-2抑制剂（NS 398）降低了来自用载体或HS微粒处理的小鼠的动脉中5-羟色胺的收缩作用;然而，在用MetS微粒处理的小鼠中没有观察到这一点，可能是由于MetS微粒增强前列环素的能力。MetS微粒介导的血管功能障碍与活性氧（ROS）增加和NADPH氧化酶亚基表达增强有关。促炎途径Fas/FasL的中和完全防止了血管低反应性和MetS微粒增强诱导型NO合酶和单核细胞趋化蛋白-1（MCP-1）的能力。我们的数据提供的证据表明，MetS患者的微粒诱导离体血管功能障碍，通过增加ROS和NO的释放，并通过改变环加氧酶代谢产物和MCP-1通过Fas/FasL途径。
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 hyporeactivity 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 proinflammatory 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.