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

Publication date: Available online 17 February 2019Source: Life SciencesAuthor(s): Yan-Ling Cui, Run-Qing Xue, Xi-He, Ming-Zhao, Xiao-Jiang Yu, Long-Zhu Liu, Qing Wu, Si-Yang, Dong-Ling Li, Wei-Jin ZangAbstractAimsObesity 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.Main methodsHigh 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.Key findingsPYR 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 selecti...
Source: Life Sciences - Category: Biology Source Type: research