The interleukin-1 receptor antagonist anakinra improves endothelial dysfunction in streptozotocin-induced diabetic rats

Cardiovascular Diabetology

Carlos F Sánchez-Ferrer³  Concepción Peiró³  Laura Villalobos³  Tania Romacho²  Erika Palacios¹  Susana Vallejo³ 

[1] Present address: Departamento de Ciencias de la Salud, Edificio CN208, Oficina O, Universidad de las Américas, Puebla, México;Present address: Paul Langerhans-Group, Integrative Physiology, German Diabetes Center, Auf’m Hennekamp 65, Düsseldorf, 40225, Germany;Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, Calle Arzobispo Morcillo 4, Madrid, 29029, Spain

关键词: Vascular inflammation;    Interleukin-1β;    Anakinra;    Nuclear factor-κB;    NADPH oxidase;    Endothelial dysfunction;    Diabetes mellitus;   

Others  :  1118927
DOI  :  10.1186/s12933-014-0158-z

 received in 2014-05-28, accepted in 2014-11-21,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Vallejo et al.; licensee BioMed Central.

【 图 表 】

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