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.
Highlights
Endothelial dysfunction is a crucial early phenomenon in vascular diseases linked to diabetes mellitus and associated to enhanced oxidative stress
Effects of IL-1β on endothelium-dependent relaxations When isolated mesenteric microvessels from SD rats were incubated for 2 hours with IL-1β (1 to 10 ng/mL), there were no changes in the contractile responses to 1 μmol/L NA (10.19 ± 0.90, 12.13 ± 0.81, 9.09 ± 1.24, 11.85 ± 1.21, and 10.51 ± 3.56 mNewtons, for control and segments treated with 1, 2.5, 5, and 10 ng/mL IL-1β, respectively), while a concentration-dependent impairment of the endothelium-derived relaxations induced by ACh was observed (Figure 2A)
The endothelium impairment induced by 2.5 ng/mL IL-1β was blunted by pre-incubating the vascular segments with the Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor apocynin (10 μmol/L) (Figure 3B) and partially prevented by the anion superoxide scavenger tempol (100 μmol/L) (Figure 3C)
Summary
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. In addition to oxidative stress, other mechanisms are participating in diabetic vasculopathy, including insulin resistance and increased systemic and vascular inflammation [10]. In this context, increasing evidence supports the participation of pro-inflammatory cytokines in the development of vascular diseases, such as atherosclerosis and diabetic vasculopathy [11,12,13,14]. The antagonism of IL-1 receptors has been recently proposed as a pharmacological target for the treatment of type 2 diabetes [19,20,21]
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