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

Cardiovascular Diabetology

Original Investigation

Long Chen¹  Qin Wei¹  Xiaomei Ren²  Liqun Ren²  Hua Shao³  Naifeng Liu⁴ 

[1] Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, No. 87, Dingjiaqiao Road, 210009, Nanjing, China;Department of Geriatrics, Zhongda Hospital, School of Medicine, Southeast University, No. 87, Dingjiaqiao Road, 210009, Nanjing, China;Department of Pharmacy, Zhongda Hospital, Southeast University, No. 87, Dingjiaqiao Road, 210009, Nanjing, China;School of Medicine, Southeast University, No. 87, Dingjiaqiao Road, 210009, Nanjing, China;

关键词: Advanced glycation end-products;    Endothelial nitric oxide synthase;    Oxidative stress;    Endothelial dysfunction;   

DOI  :  10.1186/s12933-017-0531-9

 received in 2016-12-23, accepted in 2017-04-04,  发布年份 2017

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© The Author(s) 2017