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

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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 2009

Keywords

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

ASJC Scopus subject areas

  • Internal Medicine

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    Lima, V. V., Giachini, F. R. C., Choi, H., Carneiro, F. S., Carneiro, Z. N., Fortes, Z. B., Carvalho, M. H. C., Webb, R. C., & 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