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. 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. 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.

Key points: Two distinct angiotensin‐(1–7) [Ang‐(1–7)] receptor blockers, A779 and d‐Pro‐Ang‐(1–7), can completely prevent Ang‐(1–7)‐induced vasorelaxation. Genetic deficiency of Mas completely prevents vascular responses to Ang‐(1–7). Genetic deficiency of Mas completely prevents vascular responses to other NO‐dependent vasorelaxants (bradykinin). Mas plays a key role in NO‐mediated vasodilatation by modulating vasorelaxant‐mediated phosphorylation of endothelial nitric oxide synthase in endothelial cells. Abstract  The heptapeptide angiotensin‐(1–7) is a biologically active metabolite of angiotensin II, the predominant peptide of the renin–angiotensin system. Recently, we have shown that the receptor Mas is associated with angiotensin‐(1–7)‐induced signalling and mediates, at least in part, the vasodilatory properties of angiotensin‐(1–7). However, it remained controversial whether an additional receptor could account for angiotensin‐(1–7)‐induced vasorelaxation. Here, we used two different angiotensin‐(1–7) antagonists, A779 and d‐Pro‐angiotensin‐(1–7), to address this question and also to study their influence on the vasodilatation induced by bradykinin. Isolated mesenteric microvessels from both wild‐type and Mas‐deficient C57Bl/6 mice were precontracted with noradrenaline, and vascular reactivity to angiotensin‐(1–7) and bradykinin was subsequently studied using a small‐vessel myograph. Furthermore, mechanisms for Mas effects were investigated in primary human umbilical vein endothelial cells. Both angiotensin‐(1–7) and bradykinin triggered a concentration‐dependent vasodilatation in wild‐type microvessels, which was absent in the presence of a nitric oxide synthase inhibitor. In these vessels, the pre‐incubation with the Mas antagonists A779 or d‐Pro‐angiotensin‐(1–7) totally abolished the vasodilatory capacity of both angiotensin‐(1–7) and bradykinin, which was nitric oxide mediated. Accordingly, Mas‐deficient microvessels lacked the capacity to relax in response to either angiotensin‐(1–7) or bradykinin. Pre‐incubation of human umbilical vein endothelial cells with A779 prevented bradykinin‐mediated NO generation and NO synthase phosphorylation at serine 1177. The angiotensin‐(1–7) antagonists A779 and d‐Pro‐angiotensin‐(1–7) equally block Mas, which completely controls the angiotensin‐(1–7)‐induced vasodilatation in mesenteric microvessels. Importantly, Mas also appears to be a critical player in NO‐mediated vasodilatation induced by renin–angiotensin system‐independent agonists by altering phosphorylation of NO synthase.

Chagas cardiomyopathy (CC), caused by the protozoan Trypanosoma cruzi, is an important cause of cardiovascular morbidity and mortality in developing countries. It is estimated that 6 to 7 million people worldwide are infected, and it is predicted that it will be responsible for 200,000 deaths by 2025. The World Health Organization (WHO) considers Chagas disease (CD) as a Neglected Tropical Disease (NTD), which must be acknowledged and detected in time, as it remains a clinical and diagnostic challenge in both endemic and non-endemic regions and at different levels of care. The literature on CC was analyzed by searching different databases (Medline, Cochrane Central, EMBASE, PubMed, Google Scholar, EBSCO) from 1968 until October 2022. Multicenter and bioinformatics trials, systematic and bibliographic reviews, international guidelines, and clinical cases were included. The reference lists of the included papers were checked. No linguistic restrictions or study designs were applied. This review is intended to address the current incidence and prevalence of CD and to identify the main pathogenic mechanisms, clinical presentation, and diagnosis of CC.