title: O-GlcNAcylation contributes to augmented vascular reactivity induced by endothelin 1.
abstract: 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.
authors: Medical College of Georgia, Department of Physiology, 1120 Fifteenth St, CA-3141, Augusta, GA 30912-3000, USA. vlima@mcg.edu
authors: Victor V
authors: VV
authors: Lima
authors: Fernanda R
authors: FR
authors: Giachini
authors: Fernando S
authors: FS
authors: Carneiro
authors: Zidonia N
authors: ZN
authors: Carneiro
authors: Mohamed A
authors: MA
authors: Saleh
authors: David M
authors: DM
authors: Pollock
authors: Zuleica B
authors: ZB
authors: Fortes
authors: Maria Helena C
authors: MH
authors: Carvalho
authors: Adviye
authors: A
authors: Ergul
authors: R Clinton
authors: RC
authors: Webb
authors: Rita C
authors: RC
authors: Tostes
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism*; D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism / Q000502:physiology*; D000077868:Atrasentan; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D003900:Desoxycorticosterone; D004357:Drug Synergism; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006023:Glycoproteins / Q000378:metabolism; D006031:Glycosylation; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D019332:Endothelin-1; D006023:Glycoproteins; D011759:Pyrrolidines; D014662:Vasoconstrictor Agents; D010656:Phenylephrine; D003900:Desoxycorticosterone; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase; D000077868:Atrasentan; D000117:Acetylglucosamine