Oxidative stress markers in patients with hereditary angioedema

Abstract

A b s t r a c t Introduction: Hereditary angioedema due to C1-INH deficiency (C1-INH-HAE)or with normal C1-INH is characterized by recurrent swellings due to uncontrolled production of vasoactive mediators, among which bradykinin (BK) is crucial. Through the binding and activation of the two human BK-receptors, kinins may have dual beneficial and deleterious effects in vascular and inflammation physiopathology by inducing oxidative stress. We aimed to assess the serum concentrations of advanced glycation end products (AGEs) and advanced oxidation protein products (AOPPs) in patients affected by HAE. Material and methods: Blood samples were collected to measure the serum concentrations of AGEs and AOPPs by spectrofluorimetric and spectrophotometric methods in patients affected by C1-INH-HAE and FXII-HAE during the remission state. Results: We showed that the circulating levels of AOPPs observed on control group (0.94 (0.36) nmol/ mg) were significantly lower than those observed on the C1-INH-HAE group (1.68 (0.47) nmol/mg; p = 0.002) and FXII-HAE (1.50 (0.27) nmol/mg; p = 0.001). Moreover, the circulating levels of AGEs were significantly higher in C1- ) AU/g; p = 0.02) than the FXII group (141.48 (89.59) AU/g), thus demonstrating a state of heightened oxidative stress. Conclusions: Our observations show additional underlying events involved in HAE and are of central importance for further investigations of differences in bradykinin receptors signaling among the two disease subgroups.

Bradykinin and oxidative stress in patients with hereditary angioedema due to C1 inhibitor deficiency

“…24,25,[35][36][37][38][39] Our results concerning oxidative stress in C1--INH -HAE as well as the effect of bradykinin on oxidative stress in PBMCs in this patient population were presented as preliminary findings during 2018 Bradykinin Symposium in Berlin. 40 They are generally consistent with the recent study by Del Giacco et al, 18 who indicated Our results concerning the effect of exogenous bradykinin on basal and H 2 O 2 -induced ROS levels in PBMCs in patients with C1 -INH -HAE showed that bradykinin exerted a significant antioxidant effect in this group of patients. The lack of antioxidant bradykinin action in healthy controls may be associated with normal C1 -INH levels or may indicate that this effect manifests only in the case of increased oxidative stress.…”

“…At the same time, bradykinin was proved to stimulate the activity of the antioxidant enzymes superoxide dismutase and catalase in endothelial cells. 18,49 This recent evidence corroborates a previous study reporting an increase in superoxide dismutase, catalase, and glutathione peroxidase activity in hyperglycemic rats. 47,48 On the basis of these findings as well as our data, a hypothesis may be proposed that one of the various bradykinin effects is to maintain the redox balance.…”

“…A full explanation of the role of oxidative stress and antioxidant action of bradykinin might have important implications for the prevention and treatment of C1 -INH -HAE. 18,35,40 In conclusion, our study is the first to reveal a significant increase in basal and H 2 O 2 -induced ROS levels in patients with C1 -INH -HAE as well as antioxidant action of exogenous bradykinin. It seems also that in patients with C1 -INH -HAE, elevated oxidative stress may induce an increase of bradykinin levels as a natural antioxidant as a result of a feedback reaction provoking an angioedema attack.…”

“…27,46 Data from studies on the vascular system of diabetic rats showed that B 1 R enhances superoxide anion radical formation by activating NADPH oxidase. 18,27,46 Moreover, it has been shown that oxidative stress caused by elevated superoxide anion production induces expression of the kinin B 1 R in the liver and brain of diabetic rats. [46][47][48] In light of recent findings, the cooperation between G protein-coupled receptors makes the signal transduction pathways of active peptides even more complex.…”

“…[46][47][48] In light of recent findings, the cooperation between G protein-coupled receptors makes the signal transduction pathways of active peptides even more complex. 18,49 Thus, oligomerization of bradykinin receptors and other receptors may modulate physiological processes and partially account for the discrepancies between bradykinin effects reported in different studies. Therefore, the expression and activation of B 1 R and B 2 R in patients with C1 -INH -HAE should be investigated in further studies.…”