O-GlcNAcylation contributes to augmented vascular reactivity induced by endothelin 1.

Lima VV, Giachini FR, Carneiro FS, Carneiro ZN, Saleh MA, Pollock DM, Fortes ZB, Carvalho MH, Ergul A, Webb RC, Tostes RC
Hypertension. 2010 55 (1): 180-8

PMID: 19948983 · PMCID: PMC2808689 · DOI:10.1161/HYPERTENSIONAHA.109.143818

O-GlcNAcylation augments vascular contractile responses, and O-GlcNAc-proteins are increased in the vasculature of deoxycorticosterone-acetate salt rats. Because 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 mumol/L) produced a time-dependent increase in O-GlcNAc levels and decreased expression of O-GlcNAc transferase and beta-N-acetylglucosaminidase, key enzymes in the O-GlcNAcylation process. Overnight treatment of aortas with ET-1 increased phenylephrine vasoconstriction (maximal effect [in moles]: 19+/-5 versus 11+/-2 vehicle). ET-1 effects were not observed when vessels were previously instilled with anti-O-GlcNAc transferase antibody or after incubation with an O-GlcNAc transferase inhibitor (3-[2-adamantanylethyl]-2-[{4-chlorophenyl}azamethylene]-4-oxo-1,3-thiazaperhyd roine-6-carboxylic acid; 100 mumol/L). Aortas from deoxycorticosterone-acetate salt rats, which exhibit increased prepro-ET-1, displayed increased contractions to phenylephrine and augmented levels of O-GlcNAc proteins. Treatment of deoxycorticosterone-acetate salt rats with an endothelin A antagonist abrogated augmented vascular levels of O-GlcNAc and prevented increased phenylephrine vasoconstriction. Aortas from rats chronically infused with low doses of ET-1 (2 pmol/kg per minute) exhibited increased O-GlcNAc proteins and enhanced phenylephrine responses (maximal effect [in moles]: 18+/-2 versus 10+/-3 control). These changes are similar to those induced by O-(2-acetamido-2-deoxy-d-glucopyranosylidene) amino-N-phenylcarbamate, an inhibitor of beta-N-acetylglucosaminidase. Systolic blood pressure (in millimeters of mercury) was similar between control and ET-1-infused rats (117+/-3 versus 123+/-4 mm Hg; 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.

MeSH Terms (22)

Acetylglucosamine Animals Aorta, Thoracic Atrasentan Blood Pressure Blotting, Western Desoxycorticosterone Drug Synergism Endothelin-1 Glycoproteins Glycosylation Hypertension In Vitro Techniques Male N-Acetylglucosaminyltransferases Phenylephrine Pyrrolidines Rats Rats, Wistar Time Factors Vasoconstriction Vasoconstrictor Agents

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