Impaired vasodilator activity in deoxycorticosterone acetate-salt hypertension is associated with increased protein O-GlcNAcylation

Victor V. Lima, Fernanda R.C. Giachini, Hyehun Choi, Fernando S. Carneiro, Zidonia N. Carneiro, Zuleica B. Fortes, Maria Helena C. Carvalho, R. Clinton Webb, Rita C. Tostes

Research output: Contribution to journalArticle

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Abstract

Hyperglycemia, which increases O-linked β-N-acetylglucosamine (O-GlcNAc) proteins, leads to changes in vascular reactivity. Because vascular dysfunction is a key feature of arterial hypertension, we hypothesized that vessels from deoxycorticosterone acetate and salt (DOCA-salt) rats exhibit increased O-GlcNAc proteins, which is associated with increased reactivity to constrictor stimuli. Aortas from DOCA rats exhibited increased contraction to phenylephrine (E max [mN] = 17.6±4 versus 10.7±2 control; n=6) and decreased relaxation to acetylcholine (47.6±6% versus 73.2±10% control; n=8) versus arteries from uninephrectomized rats. O-GlcNAc protein content was increased in aortas from DOCA rats (arbitrary units=3.8±0.3 versus 2.3±0.3 control; n=5). PugNAc (O-GlcNAcase inhibitor; 100 μmol/L; 24 hours) increased vascular O-GlcNAc proteins, augmented phenylephrine vascular reactivity (18.2±2 versus 10.7±3 vehicle; n=6), and decreased acetylcholine dilation in uninephrectomized (41.4±6 versus 73.2±3 vehicle; n=6) but not in DOCA rats (phenylephrine, 16.5±3 versus 18.6±3 vehicle, n=6; acetylcholine, 44.7±8 versus 47.6±7 vehicle, n=6). PugNAc did not change total vascular endothelial nitric oxide synthase levels, but reduced endothelial nitric oxide synthase Ser-1177 and Akt Ser-473 phosphorylation (P<0.05). Aortas from DOCA rats also exhibited decreased levels of endothelial nitric oxide synthase Ser-1177 and Akt Ser-473(P<0.05) but no changes in total endothelial nitric oxide synthase or Akt. Vascular O-GlcNAc-modified endothelial nitric oxide synthase was increased in DOCA rats. Blood glucose was similar in DOCA and uninephrectomized rats. Expression of O-GlcNAc transferase, glutamine:fructose- 6-phosphate amidotransferase, and O-GlcNAcase, enzymes that directly modulate O-GlcNAcylation, was decreased in arteries from DOCA rats (P<0.05). This is the first study showing that O-GlcNAcylation modulates vascular reactivity in normoglycemic conditions and that vascular O-GlcNAc proteins are increased in DOCA-salt hypertension. Modulation of increased vascular O-GlcNAcylation may represent a novel therapeutic approach in mineralocorticoid hypertension.

Original languageEnglish (US)
Pages (from-to)166-174
Number of pages9
JournalHypertension
Volume53
Issue number2
DOIs
StatePublished - Feb 1 2009

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Desoxycorticosterone
Desoxycorticosterone Acetate
Vasodilator Agents
Blood Vessels
Acetates
Salts
Hypertension
Nitric Oxide Synthase Type III
Proteins
Phenylephrine
Acetylcholine
Aorta
Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing)
Arteries
Mineralocorticoids
Acetylglucosamine
Hyperglycemia
Blood Glucose
Dilatation
Phosphorylation

Keywords

  • DOCA-salt
  • O-linked N-acetylglucosaminylation
  • Vascular reactivity
  • eNOS

ASJC Scopus subject areas

  • Internal Medicine

Cite this

Lima, V. V., Giachini, F. R. C., Choi, H., Carneiro, F. S., Carneiro, Z. N., Fortes, Z. B., ... Tostes, R. C. (2009). Impaired vasodilator activity in deoxycorticosterone acetate-salt hypertension is associated with increased protein O-GlcNAcylation. Hypertension, 53(2), 166-174. https://doi.org/10.1161/HYPERTENSIONAHA.108.116798

Impaired vasodilator activity in deoxycorticosterone acetate-salt hypertension is associated with increased protein O-GlcNAcylation. / Lima, Victor V.; Giachini, Fernanda R.C.; Choi, Hyehun; Carneiro, Fernando S.; Carneiro, Zidonia N.; Fortes, Zuleica B.; Carvalho, Maria Helena C.; Webb, R. Clinton; Tostes, Rita C.

In: Hypertension, Vol. 53, No. 2, 01.02.2009, p. 166-174.

Research output: Contribution to journalArticle

Lima, VV, Giachini, FRC, Choi, H, Carneiro, FS, Carneiro, ZN, Fortes, ZB, Carvalho, MHC, Webb, RC & Tostes, RC 2009, 'Impaired vasodilator activity in deoxycorticosterone acetate-salt hypertension is associated with increased protein O-GlcNAcylation', Hypertension, vol. 53, no. 2, pp. 166-174. https://doi.org/10.1161/HYPERTENSIONAHA.108.116798
Lima, Victor V. ; Giachini, Fernanda R.C. ; Choi, Hyehun ; Carneiro, Fernando S. ; Carneiro, Zidonia N. ; Fortes, Zuleica B. ; Carvalho, Maria Helena C. ; Webb, R. Clinton ; Tostes, Rita C. / Impaired vasodilator activity in deoxycorticosterone acetate-salt hypertension is associated with increased protein O-GlcNAcylation. In: Hypertension. 2009 ; Vol. 53, No. 2. pp. 166-174.
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AU - Choi, Hyehun

AU - Carneiro, Fernando S.

AU - Carneiro, Zidonia N.

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AU - Webb, R. Clinton

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N2 - Hyperglycemia, which increases O-linked β-N-acetylglucosamine (O-GlcNAc) proteins, leads to changes in vascular reactivity. Because vascular dysfunction is a key feature of arterial hypertension, we hypothesized that vessels from deoxycorticosterone acetate and salt (DOCA-salt) rats exhibit increased O-GlcNAc proteins, which is associated with increased reactivity to constrictor stimuli. Aortas from DOCA rats exhibited increased contraction to phenylephrine (E max [mN] = 17.6±4 versus 10.7±2 control; n=6) and decreased relaxation to acetylcholine (47.6±6% versus 73.2±10% control; n=8) versus arteries from uninephrectomized rats. O-GlcNAc protein content was increased in aortas from DOCA rats (arbitrary units=3.8±0.3 versus 2.3±0.3 control; n=5). PugNAc (O-GlcNAcase inhibitor; 100 μmol/L; 24 hours) increased vascular O-GlcNAc proteins, augmented phenylephrine vascular reactivity (18.2±2 versus 10.7±3 vehicle; n=6), and decreased acetylcholine dilation in uninephrectomized (41.4±6 versus 73.2±3 vehicle; n=6) but not in DOCA rats (phenylephrine, 16.5±3 versus 18.6±3 vehicle, n=6; acetylcholine, 44.7±8 versus 47.6±7 vehicle, n=6). PugNAc did not change total vascular endothelial nitric oxide synthase levels, but reduced endothelial nitric oxide synthase Ser-1177 and Akt Ser-473 phosphorylation (P<0.05). Aortas from DOCA rats also exhibited decreased levels of endothelial nitric oxide synthase Ser-1177 and Akt Ser-473(P<0.05) but no changes in total endothelial nitric oxide synthase or Akt. Vascular O-GlcNAc-modified endothelial nitric oxide synthase was increased in DOCA rats. Blood glucose was similar in DOCA and uninephrectomized rats. Expression of O-GlcNAc transferase, glutamine:fructose- 6-phosphate amidotransferase, and O-GlcNAcase, enzymes that directly modulate O-GlcNAcylation, was decreased in arteries from DOCA rats (P<0.05). This is the first study showing that O-GlcNAcylation modulates vascular reactivity in normoglycemic conditions and that vascular O-GlcNAc proteins are increased in DOCA-salt hypertension. Modulation of increased vascular O-GlcNAcylation may represent a novel therapeutic approach in mineralocorticoid hypertension.

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KW - O-linked N-acetylglucosaminylation

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