on January 12, 2009
Published online before print January 12, 2009, doi: 10.1161/HYPERTENSIONAHA.108.116798
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Submitted on May 21, 2008
From the Department of Physiology (V.V.L., F.R.C.G., H.C., F.S.C., Z.N.C., R.C.W., R.C.T.), Medical College of Georgia, Augusta; and the Department of Pharmacology (F.R.C.G., F.S.C., Z.B.F., M.H.C.C., R.C.T.), Institute of Biomedical Sciences, University of Sao Paulo, Brazil. * To whom correspondence should be addressed. E-mail: vlima{at}mcg.edu.
Abstract—Hyperglycemia, which increases O-linked
Revised on June 15, 2008
Impaired Vasodilator Activity in Deoxycorticosterone Acetate-Salt Hypertension Is Associated With Increased Protein O-GlcNAcylation
Victor V. Lima*;
-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 (Emax [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 synthaseSer-1177 and AktSer-473 phosphorylation (P<0.05). Aortas from DOCA rats also exhibited decreased levels of endothelial nitric oxide synthaseSer-1177 and AktSer-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.
Key words: O-linked N-acetylglucosaminylation • DOCA-salt • eNOS • vascular reactivity