O-GlcNAc Impairs Endothelial Function In The Uterine Arteries From Virgin But Not Pregnant Rats: The Role Of GSK3?

O-GlcNAc Impairs Endothelial Function In The Uterine Arteries From Virgin But Not Pregnant Rats: The Role Of GSK3?

• Autor
• Vanessa Dela Justina
• Co-autores
• Fernanda Priviero , Rinaldo Rodrigues dos Passos Junior , Clinton Webb , Victor Vitorino Lima , Fernanda Regina Giachini
• Resumo

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  Introduction: Increased O-Linked ?-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. Methods: Pregnant (P) and non-pregnant (NP) Wistar rats (14-16 weeks old, 230-250 g) 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 and western blot were performed in UAs. Statistical analysis values were performed using Student’s t-test. Approval by the Ethics Committee (UFMT; 23108.120946/2015-83). Results: In NP rats, glucosamine treatment increased O-GlcNAc expression in UAs (5.82 fold of increase) accompanied by decreased endothelium-dependent relaxation compared to control (Emax, 56.16±11.8 vs. 76.38±11.1, respectively), which was abolished by L-NAME. Endothelial nitric oxide synthase (eNOS) activity and total Akt expression were decreased by glucosamine-treatment in NP rats (3.11 and 2.46 fold of decrease, respectively). Further, NP rats treated with glucosamine displayed increased glycogen synthase kinase 3 beta (GSK3?) activation and O-GlcNAc-transferase (OGT) expression in the UA (2.19 and 2.15 fold of increase, respectively). P rats treated with glucosamine displayed decreased O-GlcNAc in UAs (1.55 fold of decrease) and it was accompanied by improved relaxation to acetylcholine compared to control (pD2, 6.45±0.4 vs. 6.91±0.3, respectively), whereas eNOS and GSK3? 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. Conclusion: The underlying mechanism is, at least in part, dependent on Akt/GSK3?/OGT modulation. We speculate that during pregnancy, hormonal alterations play a protective role in preventing O-GlcNAcylation-induced endothelial dysfunction in the UAs.

• Palavras-chave
• O-GlcNAc; GSK3?; Relaxation.
• Modalidade
• Comunicação oral
• Área Temática
• Disfunção endotelial