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
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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