The interleukin-1 receptor antagonist anakinra improves endothelial dysfunction in streptozotocin-induced diabetic rats
Autor: | Laura A. Villalobos, Carlos F. Sánchez-Ferrer, Tania Romacho, Erika Palacios, Concepción Peiró, Susana Vallejo |
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Jazyk: | angličtina |
Předmět: |
Male
medicine.medical_specialty Endothelium medicine.medical_treatment Endocrinology Diabetes and Metabolism Inflammation Diabetic angiopathy Streptozocin Diabetes Mellitus Experimental Rats Sprague-Dawley Diabetes mellitus Internal medicine medicine Animals Endothelial dysfunction Vascular inflammation Original Investigation Anakinra NADPH oxidase business.industry Tumor Necrosis Factor-alpha NF-kappa B Receptors Interleukin-1 medicine.disease Nuclear factor-κB Interleukin-1β Disease Models Animal Interleukin 1 Receptor Antagonist Protein Oxidative Stress Endocrinology medicine.anatomical_structure Interleukin 1 receptor antagonist Cytokine Antirheumatic Agents Endothelium Vascular medicine.symptom business Reactive Oxygen Species Cardiology and Cardiovascular Medicine Diabetic Angiopathies medicine.drug |
Zdroj: | Cardiovascular Diabetology |
ISSN: | 1475-2840 |
DOI: | 10.1186/s12933-014-0158-z |
Popis: | 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. |
Databáze: | OpenAIRE |
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