IASH - O-GlcNAcylation contributes to augmented vascular reactivity induced by ET-1

• Published in: Hypertension (Dallas, Tex. 1979) Tex. 1979), 2009-11, Vol.55 (1), p.180-188
• Main Authors: Lima, Victor V., Giachini, Fernanda R., Carneiro, Fernando S., Carneiro, Zidonia N., Saleh, Mohamed A., Pollock, David M, Fortes, Zuleica B., Carvalho, Maria Helena C., Ergul, Adviye, Webb, R. Clinton, Tostes, Rita C.
• Format: Article
• Language: English
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.109.143818

O-GlcNAcylation augments vascular contractile responses and O-GlcNAc-proteins are increased in the vasculature of DOCA-salt rats. Since Endothelin-1 (ET-1) plays a major role in vascular dysfunction associated with salt-sensitive forms of hypertension, we hypothesized that ET-1-induced changes in vascular contractile responses are mediated by O-GlcNAc modification of proteins. Incubation of rat aortas with ET-1 (0.1 μM) produced a time-dependent increase in O-GlcNAc levels and decreased expression of O -GlcNAc transferase (OGT) and β-N-acetylglucosaminidase (OGA), key enzymes in the O-GlcNAcylation process. Overnight treatment of aortas with ET-1 increased phenylephrine (PE) vasoconstriction [Emax (mN)= 19±5 vs. 11±2 vehicle]. ET-1 effects were not observed when vessels were previously instilled with anti-OGT antibody or after incubation with an OGT inhibitor (ST045849, 100μM). Aortas from DOCA-salt rats, which exhibit increased prepro-ET-1, displayed increased contractions to PE and augmented levels of O-GlcNAc proteins. Treatment of DOCA-salt rats with an ET A antagonist abrogated augmented vascular levels of O-GlcNAc and prevented increased PE vasoconstriction. Aortas from rats chronically infused with low doses of ET-1 (2pmol/Kg/min) exhibited increased O-GlcNAc-proteins and enhanced PE responses [Emax (mN) = 18±2 vs. 10±3 control]. These changes are similar to those induced by PugNAc, an inhibitor of OGA. Systolic blood pressure (mmHg) was similar between control and ET-1-infused rats (117±3 vs. 123±4; respectively). We conclude that ET-1 indeed augments O-GlcNAc levels and that this modification contributes to the vascular changes induced by this peptide. Increased vascular O-GlcNAcylation by ET-1 may represent a mechanism for hypertension-associated vascular dysfunction or other pathological conditions associated with increased levels of ET-1.