Abstract
BackgroundAdvanced glycation end-products (AGEs) are elevated under diabetic conditions and associated with insulin resistance, endothelial dysfunction and vascular inflammation in humans. It has been demonstrated that AGEs evoke oxidative and inflammatory reactions in endothelial cells through the interaction with a receptor for AGEs (RAGE). Here, we aimed to identify the cellular mechanisms by which AGEs exacerbate the endothelial dysfunction in human coronary artery endothelial cells (HCAECs).Methods30 type 2 diabetic patients with or without coronary artery atherosclerosis were recruited for this study. Plasma levels of AGE peptides (AGE-p) were analyzed using flow injection assay. Endothelial function was tested by brachial artery flow-mediated vasodilatation (FMD). Further investigations were performed to determine the effects and mechanisms of AGEs on endothelial dysfunction in HCAECs.ResultsAGE-p was inversely associated with FMD in diabetic patients with coronary artery atherosclerosis in our study. After treated with AGEs, HCAECs showed significant reductions of eNOS mRNA and protein levels including eNOS and phospho-eNOS Ser1177, eNOS mRNA stability, eNOS enzyme activity, and cellular nitric oxide (NO) levels, whereas superoxide anion production was significantly increased. In addition, AGEs significantly decreased mitochondrial membrane potential, ATP content and catalase and superoxyde dismutase (SOD) activities, whereas it increased NADPH oxidase activity. Treatment of the cells with antioxidants SeMet, SOD mimetic MnTBAP and mitochondrial inhibitor thenoyltrifluoroacetone (TTFA) effectively blocked these effects induced by AGEs. AGEs also increased phosphorylation of the mitogen-activated protein kinases p38 and ERK1/2, whereas the specific inhibitors of p38, ERK1/2, and TTFA effectively blocked AGEs-induced reactive oxygen species production and eNOS downregulation.ConclusionsAGEs cause endothelial dysfunction by a mechanism associated with decreased eNOS expression and increased oxidative stress in HCAECs through activation of p38 and ERK1/2.
Highlights
Advanced glycation end-products (AGEs) are elevated under diabetic conditions and associated with insulin resistance, endothelial dysfunction and vascular inflammation in humans
AGE‐p was inversely associated with FMD in type 2 diabetic patients with coronary artery atherosclerosis To investigate of relationship between AGE peptides (AGE-p) and FMD in type 2 diabetic patients with or without coronary artery atherosclerosis, levels of plasma AGE-p and flow-mediated vasodilatation were tested
These result showed that the levels of plasma AGE-p were inversely associated with flow-mediated vasodilatation in our subjects (R2 = −0.61, P < 0.05), whereas other cardiometabolic risk factors, including age, fasting plasma glucose, HbA1C, blood pressure, lipid parameters and body mass index, were not associated with FMD
Summary
Advanced glycation end-products (AGEs) are elevated under diabetic conditions and associated with insulin resistance, endothelial dysfunction and vascular inflammation in humans. We aimed to identify the cellular mechanisms by which AGEs exacerbate the endothelial dysfunction in human coronary artery endothelial cells (HCAECs). Endothelial dysfunction has largely been assessed as alterations of endothelium-dependent vasorelaxation and gene expression. AGEs can bind to its receptor RAGE, triggering the production of several proinflammatory cytokines and chemokines, inducing oxidative stress via the activation of NF-kB [6]. AGEs was able to reduce NO production and eNOS expression under the condition of high glucose [5]. Despite accumulating evidence pointing to a causal role of AGEs-induced lesion in the pathogenesis of diabetic vascular disorder, the molecular mechanisms involved in endothelial dysfunction remains poorly understood
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