Disfunción endotelial asociada a la diabetes mellitus interacción entre inflamación e hiperglucemia

Resumen

Diabetic vasculopathy is a chronic low-grade inflammatory disease associated to hyperglycemia. Endothelial dysfunction is an early manifestation of the diabetic vasculopathy and controversial results exist at present to explain how the elevation of D-glucose can impairs the endothelium-mediated vasodilatations. On the other hand, both in type 1 and type 2 diabetes mellitus, a prominent role for pro-inflammatory cytokines, such as interleukin-1¿ (IL- 1¿), has been proposed for the pathogenesis of the disease, as well as in the development of diabetic vasculopathy. Nevertheless, little it is known concerning on the capacity of these cytokines to induce endothelial dysfunction, as well as its relevance in diabetes mellitus. In the first part of the study, performed in mesenteric microvessels from control Sprague-Dawley rats, it was demonstrated that the mere increase of extracellular D-glucose concentrations was not sufficient to induce an impairment of the endothelium-dependent relaxations to ACh. Nevertheless, the pre-incubation of the microvessels with the proinflammatory cytokine IL-1¿ during 30 min or 2 h produced a concentration-dependent endothelial dysfunction in these microvessels. The endothelial dysfunction induced by IL-1¿¿ was potentiated by the increase of the extracellular concentrations of D-glucose¿¿The treatment of the rat mesenteric microvessels with the recombinant human IL-1 receptors antagonist, anakinra (AK), produced a concentration-dependent improvement of the endothelial dysfunction caused by IL-1¿, both in normal D-glucose medium as in the presence of high concentrations of the hexose. The endothelial dysfunction induced by IL-1¿¿ as well as its enhancement by high Dglucose, was associated with an increase of the NADPH-oxidase enzymatic activity, measured by lucigenin chemiluminescence, which can produce O- 2 that interferes with the endothelium-dependent relaxations mediated by NO. Moreover, the endothelial dysfunction by IL-1¿ was improved by treating the vessels with the O- 2 scavenger tempol or the NADPH-oxidase inhibitor apocynin, and by inhibiting the pentose phosphate pathway (necessary for the supply of NADPH) with 6-ANAM. In the second part of the study, the endothelial function was tested in an acute model of diabetes type 1, induced by the administration of streptozotocin. In mesenteric microvessels II obtained from this experimental model of diabetes, an impairment of the endotheliumdependent relaxations induced by ACh was produced after two weeks of evolution of the disease. The endothelial dysfunction observed in these rats was mediated by an increase of the oxidative stress associated to the activation of the NADPH-oxidase enzyme, measured by lucigenin chemiluminescence studies. As occurs with the alteration of the endothelial function caused by IL-1¿, the diabetic endothelial dysfunction was improved by treating the vessels with the O- 2 scavenger tempol or the NADPH-oxidase inhibitor apocynin, and by inhibiting the pentose phosphate pathway (necessary for the supply of NADPH) with 6-ANAM. In this acute model of experimental diabetes, the endothelial function of the mesenteric microvessels was restored by the treatment of the animals with the competitive antagonist of the IL-1 receptors, anakinra. The improvement of the endothelial function was associated to an inhibition of the NADPH-oxidase activity in the vessels obtained of these treated animals. Therefore, the pro-inflammatory cytokine IL-1¿ can have a relevant role in the endothelial dysfunction associated to the diabetes mellitus, although its plasmatic levels were not significantly increased in the diabetic animals. In conclusion, these findings indicate that hyperglycemia by itself is not sufficient to directly produce endothelial dysfunction, although it can potentiate the effects of an ongoing inflammatory response, produced by cytokines like IL-1¿, which could be mediating the endothelial dysfunction associated to the diabetes mellitus, in the same way that occurs in different inflammatory processes related to the disease. The mechanism activated by these cytokines can be the vascular NADPH-oxidase enzyme, with the consequent increase in the production of O- 2. Finally, this study suggests that the therapeutic approaches for the treatment of the diabetic vasculopathy should not only diminish the hyperglycemia, but also reduce the vascular pro-inflammatory environment. The antagonists of the receptors for IL-1 seem to be a promising possibility.