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

Cardiovasc Diabetol. 2014 Dec 18;13:158. doi: 10.1186/s12933-014-0158-z.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antirheumatic Agents / pharmacology*
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetic Angiopathies / drug therapy*
  • Disease Models, Animal
  • Endothelium, Vascular / drug effects*
  • Inflammation / drug therapy
  • Interleukin 1 Receptor Antagonist Protein / metabolism*
  • Interleukin 1 Receptor Antagonist Protein / pharmacology*
  • Male
  • NF-kappa B / drug effects
  • NF-kappa B / metabolism
  • Oxidative Stress / drug effects
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / metabolism
  • Receptors, Interleukin-1 / drug effects
  • Streptozocin
  • Tumor Necrosis Factor-alpha / metabolism


  • Antirheumatic Agents
  • Interleukin 1 Receptor Antagonist Protein
  • NF-kappa B
  • Reactive Oxygen Species
  • Receptors, Interleukin-1
  • Tumor Necrosis Factor-alpha
  • Streptozocin