Synergistic Efffect Of High Uric Acid And Angiotensin â…¡ On Vascular Endothelial Cells Injury

Background and objectives: With the changes of diet and lifestyle, obesity, diabetes,hypertension, high cholesterol, hyperuricemia and other metabolic diseases areincreasing in prevalence throughout the world. The main features of metabolicsyndrome includes obesity, insulin resistance, hypertension, dyslipidemia. Althoughmany mechanisms have been proposed, oxidative stress is the most important.Epidemiological studies have demonstrated that hyperuricmia are commonly seen inpatients with the metabolic syndrome. Uric acid is a powerful antioxidant, how it canlead to endothelial injury? In our previous study, we found normal levels of uric acidhas the antioxidant function, but high uric acid could result in the endothelialdysfunction. We hypothesized that elevated uric acid levels may be a protectivecompensatory response to increased oxidative stress, but the excessive rise will leadto endothelial dysfunction. Many studies have shown that the renin-angiotensinsystem (RAS) is activated in metabolic syndrome. It is generally known that the coreof the RAS system is angiotensin Ⅱ (Ang Ⅱ), which leads to endothelial dysfunctionthrough the activation of oxidative stress and the activation of redox dependentsignaling pathways. Therefore, we chose Ang Ⅱ as a representative stimulator toinduce endothelial damage, spontaneously hypertensive rats (SHR) to build metabolicsyndrome model. Our aim is to clarify the relationship and the mechanisms of highuric acid and Ang Ⅱ on endothelial injury in vitro and in vivo experiments.Methods: Part I. In vitro, we stimulated the human umbilical vein endothelial cells(HUVECs-C) with HUA (600μmol/L), then stimulated with Ang Ⅱ (1×10-7mol/L). We collectd the supernatant for measuring NO levels. Western blot analysis wasperformed to assess the expression of eNOS protein levels. Confocal was used todetect the level of each group of reactive oxygen species (ROS) and its components(hydrogen peroxide, superoxide anion, singlet oxygen, hydroxyl radical,peroxynitrite). Part Ⅱ. Ten-week-old male spontaneously hypertensive rats (SHR) were feed withthe high-fat and high-glucose diets, WKY rats were used as control group. Aftereight weeks, the SHR rats were randomly divided into5groups: MS group; HUAgroup; HUA+Catalase group; HUA+PEG-SOD group; HUA+Epalrestat group.All of the groups were injected with oxonic acid and uric acid for ten days toestablish the hyperuricemia model except for the MS group. The body weight, the tailarterial blood pressure, serum lipid, blood glucose, uric acid were detected. After theend of the experiment, the levels of NO, total antioxidative capacity, hydrogenperoxide, and von Willebrand factor level were detected to evaluate the endothelialfunction and oxidative stress.Results: In vitro, we found that both Ang Ⅱ and high uric acid increased the produceof superoxide anion (O2-)、 hydrogen peroxide (H2O2) and hydroxyl radical (·OH),but the produce of singlet oxygen (1O2) was reduced in high uric acid level, increasedin Ang Ⅱ. In vivo, after eight weeks of high-fat and high-glucose diets, the bodyweight, the level of serum TG and LDL-C, fasting blood glucose were significantlyincreased. Blood pressure was in the hypertensive state. After ten days of abdominalinjection of oxonic acid and uric acid, serum uric acid levels were increased. Thelevels of NO and TAC decreased, H2O2and vWF increased in HUA group. At thesame time, catalase, PEG-SOD and aldose reductase inhibitor-epalrestat couldscavenge superoxide anion, hydrogen peroxide, and reduce the production of reactiveoxygen species, and increase the levels of NO and TAC, decrease H2O2and vWF.Conclusion: Hyperuricemia may antagonize oxidative stress caused by RAS, but theexcessive uric acid and Ang II caused the damage to the endothelium together. Themajor component of reactive oxygen species are O2-and H2O2, which lead toendothelial injury. Blocking aldose reductase pathway or scavenging O2-and H2O2can protect endothelial function. These provides a theoretical basis for the preventionand treatment of endothelial dysfunction caused by metabolic syndrome,hyperuricemia, and other metabolic diseases.