TY - JOUR
T1 - O-GlcNAc impairs endothelial function in uterine arteries from virgin but not pregnant rats
T2 - The role of GSK3β
AU - Dela Justina, Vanessa
AU - Priviero, Fernanda
AU - dos Passos, Rinaldo Rodrigues
AU - Webb, R. Clinton
AU - Lima, Victor Vitorino
AU - Giachini, Fernanda R.
N1 - Funding Information:
This study was supported by Fundação de Amparo à Pesquisa do Estado de Mato Grosso ( FAPEMAT , 0324,552/2018 to F.R.G.); Conselho Nacional de Desenvolvimento Científico e Tecnológico ( CNPq , 305,823/2015–9 to F.R.G); National Institutes of Health (NIH, PO1 HL134604 to R.C.W.); Coordenação de Aperfeiçoamento de Pessoal de Nível Superior ( CAPES , 88881.190484/2018-01 Scholarship to V.D.J.).
Publisher Copyright:
© 2020 Elsevier B.V.
PY - 2020/8/5
Y1 - 2020/8/5
N2 - Increased O-Linked β-N-acetylglucosamine (O-GlcNAc) is observed in several pathologies, and unbalanced O-GlcNAcylation levels favor endothelial dysfunction. Whether augmented O-GlcNAc impacts the uterine artery (UA) function and how it affects the UA during pregnancy remains to be elucidated. We hypothesized that glucosamine treatment increases O-GlcNAc, leading to uterine artery dysfunction and this effect is prevented by pregnancy. Pregnant (P) and non-pregnant (NP) Wistar rats were treated with glucosamine (300 mg/kg; i.p.) for 21 days. Concentration response-curves (CRC) to acetylcholine (in the presence or absence of L-NAME) and sodium nitroprusside were performed in UAs. In NP rats, glucosamine treatment increased O-GlcNAc expression in UAs accompanied by decreased endothelium-dependent relaxation, which was abolished by L-NAME. Endothelial nitric oxide synthase (eNOS) activity and total Akt expression were decreased by glucosamine-treatment in NP rats. Further, NP rats treated with glucosamine displayed increased glycogen synthase kinase 3 beta (GSK3β) activation and O-GlcNAc-transferase (OGT) expression in the UA. P rats treated with glucosamine displayed decreased O-GlcNAc in UAs and it was accompanied by improved relaxation to acetylcholine, whereas eNOS and GSK3β activity and total Akt and OGT expression were unchanged. Sodium nitroprusside-induced relaxation was not changed in all groups, indicating that glucosamine treatment led to endothelial dysfunction in NP rats. The underlying mechanism is, at least in part, dependent on Akt/GSK3β/OGT modulation. We speculate that during pregnancy, hormonal alterations play a protective role in preventing O-GlcNAcylation-induced endothelial dysfunction in the UAs.
AB - Increased O-Linked β-N-acetylglucosamine (O-GlcNAc) is observed in several pathologies, and unbalanced O-GlcNAcylation levels favor endothelial dysfunction. Whether augmented O-GlcNAc impacts the uterine artery (UA) function and how it affects the UA during pregnancy remains to be elucidated. We hypothesized that glucosamine treatment increases O-GlcNAc, leading to uterine artery dysfunction and this effect is prevented by pregnancy. Pregnant (P) and non-pregnant (NP) Wistar rats were treated with glucosamine (300 mg/kg; i.p.) for 21 days. Concentration response-curves (CRC) to acetylcholine (in the presence or absence of L-NAME) and sodium nitroprusside were performed in UAs. In NP rats, glucosamine treatment increased O-GlcNAc expression in UAs accompanied by decreased endothelium-dependent relaxation, which was abolished by L-NAME. Endothelial nitric oxide synthase (eNOS) activity and total Akt expression were decreased by glucosamine-treatment in NP rats. Further, NP rats treated with glucosamine displayed increased glycogen synthase kinase 3 beta (GSK3β) activation and O-GlcNAc-transferase (OGT) expression in the UA. P rats treated with glucosamine displayed decreased O-GlcNAc in UAs and it was accompanied by improved relaxation to acetylcholine, whereas eNOS and GSK3β activity and total Akt and OGT expression were unchanged. Sodium nitroprusside-induced relaxation was not changed in all groups, indicating that glucosamine treatment led to endothelial dysfunction in NP rats. The underlying mechanism is, at least in part, dependent on Akt/GSK3β/OGT modulation. We speculate that during pregnancy, hormonal alterations play a protective role in preventing O-GlcNAcylation-induced endothelial dysfunction in the UAs.
KW - Akt
KW - GSK3β
KW - O-GlcNAc
KW - Progesterone
KW - Relaxation
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U2 - 10.1016/j.ejphar.2020.173133
DO - 10.1016/j.ejphar.2020.173133
M3 - Article
C2 - 32343970
AN - SCOPUS:85084352312
SN - 0014-2999
VL - 880
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
M1 - 173133
ER -