Cholinergic drugs ameliorate endothelial dysfunction by decreasing O-GlcNAcylation via M3 AChR-AMPK-ER stress signaling.
Life Sci
; 222: 1-12, 2019 Apr 01.
Article
en En
| MEDLINE
| ID: mdl-30786250
ABSTRACT
AIMS:
Obesity is associated with increased cardiovascular morbidity and mortality. It is accompanied by augmented O-linked ß-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. MAINMETHODS:
High fat diet (HFD) model was induced obesity in mice with or without the cholinergic drug pyridostigmine (PYR, 3â¯mg/kg/d) for 22 weeks and in vitro human umbilical vein endothelial cells (HUVECs) was treated with high glucose (HG, 30â¯mM) with or without acetylcholine (ACh). KEYFINDINGS:
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.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Proteínas Quinasas
/
Acetilglucosamina
/
Endotelio Vascular
/
Colinérgicos
/
Receptor Muscarínico M3
/
Estrés del Retículo Endoplásmico
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
Life Sci
Año:
2019
Tipo del documento:
Article