Advanced glycation end-products decreases expression of endothelial nitric oxide synthase through oxidative stress in human coronary artery endothelial cells

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-017-0531-9) contains supplementary material, which is available to authorized users.

Regenerative and protective effects of calcium silicate on senescent fibroblasts induced by high glucose

“…The increased ROS production accelerates telomere shortening, induces the DNA damage response (DDR), and causes senescence growth arrest . Ren et al have shown that diabetic conditions impaired the function of endothelial cells through oxidative stress . Furthermore, Chen et al have reported that in a HG environment, endothelial cells exhibited a senescence‐associated secretory phenotype (SASP) by upregulating the NOX‐derived ROS pathway .…”

“…HG environment has been suggested to cause increased production of free radicals and consequently accelerate aging progress . Existing evidence confirms a prominent role for reactive oxygen species (ROS) as mediators of cellular aging in diabetes . Li et al have reported that HG induced fibroblast senescence in a time‐ and dose‐dependent manner .…”

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“…() associated high serum methylglyoxal, an AGE precursor, with a faster decline in attention span in elderly people (average of 71 y of age). In type 2 diabetic patients with coronary artery atherosclerosis, serum levels of AGEs were found to be inversely correlated with endothelial function (Ren et al., ). In their study of AGEs and incident cardiovascular events in patients with type 2 diabetes, Koska et al.…”

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