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

Abstract

AIMS:

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.

MAIN METHODS:

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 (HG, 30 mM) with or without acetylcholine (ACh).

KEY FINDINGS:

PYR significantly reduced body weight, blood glucose, and O-GlcNAcylation levels and attenuated vascular endothelial cells detachment in HFD-fed mice. HG 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, 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.

SIGNIFICANCE:

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.

• Authors: 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 Zang
• Journal: Life sciences (Life Sci) Vol. 222 Pg. 1-12 (Apr 01 2019) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 30786250 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Cholinergic Agents
• Cholinesterase Inhibitors
• Receptor, Muscarinic M3
• Protein Kinases
• AMP-Activated Protein Kinase Kinases
• Pyridostigmine Bromide
• Acetylcholine
• Acetylglucosamine

Topics

• AMP-Activated Protein Kinase Kinases
• Acetylcholine (pharmacology)
• Acetylglucosamine (antagonists & inhibitors, metabolism)
• Animals
• Cholinergic Agents (pharmacology)
• Cholinesterase Inhibitors (pharmacology)
• Diet, High-Fat (adverse effects)
• Dose-Response Relationship, Drug
• Endoplasmic Reticulum Stress (drug effects, physiology)
• Endothelium, Vascular (drug effects, metabolism)
• Human Umbilical Vein Endothelial Cells (drug effects, metabolism)
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Protein Kinases (metabolism)
• Pyridostigmine Bromide (pharmacology)
• Receptor, Muscarinic M3 (antagonists & inhibitors, metabolism)