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

Abstract

BackgroundEndothelial 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.ResultsIn 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.ConclusionsIn 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.

Monocytes from patients with rheumatoid arthritis and type 2 diabetes mellitus display an increased production of interleukin (IL)-1β via the nucleotide-binding domain and leucine-rich repeat containing family pyrin 3(NLRP3)-inflammasome activation: a possible implication for therapeutic decision in these patients

“…In addition, a large body of preclinical data showed that IL-1b is involved strongly in the progression of atherosclerosis [69,70]. During the inflammatory process occurring in RA, it has been shown that TNF may contribute to endothelial dysfunction [71].…”

Effects of Leucaena leucocephala (Lam.) de Wit Leaves Extracts in Culture of Human Umbilical Vein Cells

“…Total phenolic and flavonoid contents was determined, and the result showed 51.04 ± 0.91 mgGAE/g and 0.13 ± 0.01 mg of catechin/g content in dry leave extract, respectively. Likewise, other studies that found phenolic at 3.21 mg GAE/g, 33 37.38 ± 0.49 mg GAE/g, 17 78.8 g GAE/100g extract, 18 258.4±7.45 mg GAE/g, 16 7.51 to 12.06 mg GAE/g, 34 and flavonoid contents at 159.61±12.79 mg QE/g (Quercetin equivalent), 16 2.80 to 3.59 mg QE/g 34 depended on parts of plant collection and solution extracted. This compon ents suggest antioxidant activities of L. leucocephala, as confirmed in Table 1.…”

“…With histology of vascular cells, the result showed that the vascular cells were obviously dead in HUVC-induced pre-obese condition. In this condition of increasing extracellular glucose, it was suggested to induce endothelial cell dysfunction by increased activation of NADPH oxidase and IL1β, 35,36,37 which might eventually lead to senescence of the cells. When 0.05 mg/mL of leave extracts were pre-incubated in the system, the overall of vascular cells have been found resembling the control group.…”

Insights into the molecular mechanisms of diabetes-induced endothelial dysfunction: focus on oxidative stress and endothelial progenitor cells

“…This effect was partially prevented by incubation of the isolated blood vessels with Apocynin (NADPH oxidase inhibitor). Also, normal endothelial function was restored by incubation with a NADPH oxidase, cyclooxygenase-2 (COX-2), eNOS inhibitors, and superoxide dismutase [79], proving the role of oxidative stress in IL-1b-induced ED.…”