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Cholinergic drugs ameliorate endothelial dysfunction by decreasing O-GlcNAcylation via M3 AChR-AMPK-ER stress signaling

Author:
Cui, Yan-Ling, Xue, Run-Qing, Xi-He,, Ming-Zhao,, Yu, Xiao-Jiang, Liu, Long-Zhu, Wu, Qing, Si-Yang,, Li, Dong-Ling, Zang, Wei-Jin
Source:
Life sciences 2019
ISSN:
0024-3205
Subject:
AMP-activated protein kinase, acetylcholine, antagonists, apoptosis, biochemical pathways, blood glucose, butyric acid, diet, endoplasmic reticulum, endothelium, glucose, hexosamines, human umbilical vein endothelial cells, mice, models, morbidity, mortality, obesity, proteins, ribose
Abstract:
Obesity is associated with increased cardiovascular morbidity and mortality. It is accompanied by augmented O-linked β-N-acetylglucosamine (O-GlcNAc) modification of proteins via increasing hexosamine biosynthetic pathway (HBP) flux. However, the changes and regulation of the O-GlcNAc levels induced by obesity are unclear.High fat diet (HFD) model was induced obesity in mice with or without the cholinergic drug pyridostigmine (PYR, 3 mg/kg/d) for 22-weeks and in vitro human umbilical vein endothelial cells (HUVECs) was treated with high glucose with or without ACh.PYR significantly reduced body weight, blood glucose, and O-GlcNAcylation levels and attenuated vascular endothelial cell detachment in HFD-fed mice. High glucose (HG, 30 mM) addition induced endoplasmic reticulum (ER) stress and increased O-GlcNAcylation levels and apoptosis in HUVECs in a time-dependent manner. Additionally, HG decreased levels of phosphorylated AMP-activated protein kinase (AMPK). Interestingly, acetylcholine (ACh) significantly blocked damage to HUVECs induced by HG. Furthermore, the effects of ACh on HG-induced ER stress, O-GlcNAcylation, and apoptosis were prevented by treating HUVECs with 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP, a selective M3 AChR antagonist) or compound C (Comp C, an AMPK inhibitor). Treatment with 5-aminoimidazole-4-carboxamide ribose (AICAR, an AMPK activator), 4-phenyl butyric acid (4-PBA, an ER stress inhibitor), and 6-diazo-5-oxonorleucine (DON, a GFAT antagonist) reproduced a similar effect with ACh.Activation of cholinergic signaling ameliorated endothelium damage, reduced levels of ER stress, O-GlcNAcylation, and apoptosis in mice and HUVECs under obese conditions, which may function through M3 AChR-AMPK signaling.
Agid:
6328254