Impaired Vasodilator Activity in Deoxycorticosterone Acetate-Salt Hypertension Is Associated With Increased Protein O-GlcNAcylation

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 53; no. 2; pp. 166 - 174
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 01.02.2009; Lippincott Williams & Wilkins
• Subjects: Acetylcholine - pharmacology; Animals; Aorta, Thoracic - drug effects; Aorta, Thoracic - physiopathology; Arterial hypertension. Arterial hypotension; beta-N-Acetylhexosaminidases - metabolism; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Clinical manifestations. Epidemiology. Investigative techniques. Etiology; Desoxycorticosterone; Disease Models, Animal; Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) - metabolism; Hypertension - chemically induced; Hypertension - physiopathology; Male; Medical sciences; Mesenteric Arteries - drug effects; Mesenteric Arteries - physiopathology; N-Acetylglucosaminyltransferases - metabolism; Phenylephrine - pharmacology; Rats; Rats, Wistar; Vasoconstrictor Agents - pharmacology; Vasodilation - drug effects; Vasodilation - physiology; Vasodilator Agents - pharmacology; Hypertension; vascular reactivity; Cardiovascular disease; eNOS; DOCA-salt; O-linked N-acetylglucosaminylation
• ISSN: 0194-911X; 1524-4563; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.108.116798

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 (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 synthase and Akt phosphorylation (P<0.05). Aortas from DOCA rats also exhibited decreased levels of endothelial nitric oxide synthase and Akt (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.