title: The interleukin-1 receptor antagonist anakinra improves endothelial dysfunction in streptozotocin-induced diabetic rats.
abstract: BACKGROUND
  Endothelial dysfunction is a crucial early phenomenon in vascular diseases linked to diabetes mellitus and associated to enhanced oxidative stress. There is increasing evidence about the role for pro-inflammatory cytokines, like interleukin-1β (IL-1β), in developing diabetic vasculopathy. We aimed to determine the possible involvement of this cytokine in the development of diabetic endothelial dysfunction, analysing whether anakinra, an antagonist of IL-1 receptors, could reduce this endothelial alteration by interfering with pro-oxidant and pro-inflammatory pathways into the vascular wall.
  
  
  RESULTS
  In control and two weeks evolution streptozotocin-induced diabetic rats, either untreated or receiving anakinra, vascular reactivity and NADPH oxidase activity were measured, respectively, in isolated rings and homogenates from mesenteric microvessels, while nuclear factor (NF)-κB activation was determined in aortas. Plasma levels of IL-1β and tumor necrosis factor (TNF)-α were measured by ELISA. In isolated mesenteric microvessels from control rats, two hours incubation with IL-1β (1 to 10 ng/mL) produced a concentration-dependent impairment of endothelium-dependent relaxations, which were mediated by enhanced NADPH oxidase activity via IL-1 receptors. In diabetic rats treated with anakinra (100 or 160 mg/Kg/day for 3 or 7 days before sacrifice) a partial improvement of diabetic endothelial dysfunction occurred, together with a reduction of vascular NADPH oxidase and NF-κB activation. Endothelial dysfunction in diabetic animals was also associated to higher activities of the pro-inflammatory enzymes cyclooxygenase (COX) and the inducible isoform of nitric oxide synthase (iNOS), which were markedly reduced after anakinra treatment. Circulating IL-1β and TNF-α levels did not change in diabetic rats, but they were lowered by anakinra treatment.
  
  
  CONCLUSIONS
  In this short-term model of type 1 diabetes, endothelial dysfunction is associated to an IL-1 receptor-mediated activation of vascular NADPH oxidase and NF-κB, as well as to vascular inflammation. Moreover, endothelial dysfunction, vascular oxidative stress and inflammation were reduced after anakinra treatment. Whether this mechanism can be extrapolated to a chronic situation or whether it may apply to diabetic patients remain to be established. However, it may provide new insights to further investigate the therapeutic use of IL-1 receptor antagonists to obtain vascular benefits in patients with diabetes mellitus and/or atherosclerosis.
authors.affiliation: Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, Calle Arzobispo Morcillo 4, 29029, Madrid, Spain. susana.vallejo@uam.es.
authors.forename: Susana
authors.initials: S
authors.lastname: Vallejo
authors.affiliation: Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, Calle Arzobispo Morcillo 4, 29029, Madrid, Spain. erika.palacios@udlap.mx.|Present address: Departamento de Ciencias de la Salud, Edificio CN208, Oficina O, Universidad de las Américas, Puebla, México. erika.palacios@udlap.mx.
authors.forename: Erika
authors.initials: E
authors.lastname: Palacios
authors.affiliation: Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, Calle Arzobispo Morcillo 4, 29029, Madrid, Spain. tania.romacho@ddz.uni-duesseldorf.de.|Present address: Paul Langerhans-Group, Integrative Physiology, German Diabetes Center, Auf'm Hennekamp 65, 40225, Düsseldorf, Germany. tania.romacho@ddz.uni-duesseldorf.de.
authors.forename: Tania
authors.initials: T
authors.lastname: Romacho
authors.affiliation: Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, Calle Arzobispo Morcillo 4, 29029, Madrid, Spain. laura.villalobos@uam.es.
authors.forename: Laura
authors.initials: L
authors.lastname: Villalobos
authors.affiliation: Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, Calle Arzobispo Morcillo 4, 29029, Madrid, Spain. concha.peiro@uam.es.
authors.forename: Concepción
authors.initials: C
authors.lastname: Peiró
authors.affiliation: Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, Calle Arzobispo Morcillo 4, 29029, Madrid, Spain. carlosf.sanchezferrer@uam.es.
authors.forename: Carlos F
authors.initials: CF
authors.lastname: Sánchez-Ferrer
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003925:Diabetic Angiopathies / Q000188:drug therapy*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects*; D007249:Inflammation / Q000188:drug therapy; D053590:Interleukin 1 Receptor Antagonist Protein / Q000378:metabolism* / Q000494:pharmacology*; D008297:Male; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000187:drug effects; D013311:Streptozocin; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D018501:Antirheumatic Agents; D053590:Interleukin 1 Receptor Antagonist Protein; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D017472:Receptors, Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D013311:Streptozocin