Abstract
Previous reports have suggested that Ang-(1-7) may have a protective effect in endothelial cells against high glucose (HG)-induced cell injury thanks to a modulatory mechanism in the NF-κB signaling pathway. In this study, we have examined whether NF-κB-IL-1β and Heme oxygenase-1 (HO-1) pathways contribute to the protection of Ang-(1-7) against hyperglycemia-induced inflammation and oxidative stress in human umbilical vein endothelial cells (HUVECs). Our results indicate that time-varying exposures of HUVECs, from 1 h to 24 h, to high glucose concentrations result in an increased expression of phosphorylated (p)-p65 and HO-1 in a time-dependent manner. As an inhibitor of NF-κB, pyrrolidinedithiocarbamic acid (PDTC) suppressed IL-1β production induced by HG. Of note, HUVECs previously treated with Ang-(1-7) (2 μM) for 30 min before being exposed to HG concentrations significantly ameliorated the HG-increased in p-p65 and IL-1β expression; whereas obviously up-regulated the level of HO-1, along with inhibition of oxidative stress, inflammation, and the HG-induced cytotoxicity. Importantly, when HUVECs were previously treated either with PDTC or IL-1Ra for 30 min before being exposed to HG, it significantly prevented damages caused by high glucose concentrations mentioned above, while the treatment of HO-1 inhibitor Sn-protoporphyrin (SnPP) before exposure to both HG and Ang-(1-7) significantly blocked the protective effect exerted by Ang-(1-7) on endothelial cells against injuries induced by HG mentioned above. To conclude, the data of this study showed that activation and inhibition of the NF-κB-IL-1β pathway and HO-1 pathway may constitute an important defense mechanism against endothelial cell damage caused by HG concentrations. We additionally gave new evidence showing that exogenous Ang-(1-7) exerts a protective effect on HUVECs against the HG-induced cell injury via the inhibition and the activation of the NF-κB-IL-1β pathway and the HO-1 pathway, respectively.
Highlights
The predominance of diabetes mellitus (DM) is constantly incrementing, and the number of new cases is predicted to approximate 591.9 million in 2035 around the world (Guariguata et al, 2014; Shaw et al, 2010)
40 mM mannitol used for the osmotic control of high glucose did not affect the expression and translocation of NF-κB in human umbilical vein endothelial cells (HUVECs) (Figs. 1a–1f)
These results indicate that high glucose (HG) promotes NF-κB translocation into the nucleus and, activation of the NF-κB pathway in HUVECs
Summary
The predominance of diabetes mellitus (DM) is constantly incrementing, and the number of new cases is predicted to approximate 591.9 million in 2035 around the world (Guariguata et al, 2014; Shaw et al, 2010). It is important to stress that cardiovascular complications represent the most common cause of death in diabetic patients. Diabetes-induced vascular endothelium injury is a central player in the pathogenesis of medical complications of diabetes mellitus, with vascular endothelial cells playing a key role in preserving endothelial dysfunction (Capellini et al, 2010; Taguchi et al, 2014). Several studies have indicated that DM causes multiple pathological alterations in vascular endothelial cells; damages include inflammation, oxidative stress, and augmented apoptosis (Bhatt et al, 2013; Zhang et al, 2016b; Zhao et al, 2016a). The molecular mechanism of endothelial cell injury induced by hyperglycemia in DM is still unclear
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