title: High-fat diet increases O-GlcNAc levels in cerebral arteries: a link to vascular dysfunction associated with hyperlipidaemia/obesity?
abstract: Obesity and high fat intake induce alterations in vascular function and structure. Aberrant O-GlcNAcylation (O-GlcNAc) of vascular proteins has been implicated in vascular dysfunction associated with cardiovascular and metabolic diseases. In the present study, we tested the hypothesis that high-fat diet (HFD)-mediated increases in O-GlcNAc-modified proteins contribute to cerebrovascular dysfunction. O-GlcNAc-protein content was increased in arteries from male Wistar rats treated with a HFD (45% fat) for 12 weeks compared with arteries from rats on control diet (CD). HFD augmented body weight [(g) 550±10 compared with 502±10 CD], increased plasma triacylglycerols [(mg/dl) 160±20 compared with 95±15 CD] and increased contractile responses of basilar arteries to serotonin [5-hydroxytryptamine (5-HT)] [(pD2) 7.0±0.1 compared with 6.7±0.09 CD] and the thromboxane analogue 9,11-dideoxy-9α,11α-methanoepoxy prostaglandin F2α (U-46619) [(pD2) 7.2±0.1 compared with 6.8±0.09 CD]. Of importance, increased levels of O-GlcNAc [induced by 24 h-incubation of vessels with a potent inhibitor of O-GlcNAcase (OGA), O-(2-acetamido-2-deoxy-D-glucopyranosylidene)amino-N-phenylcarbamate (PugNAc)] increased basilar artery contractions in response to U-46619 [(pD2) 7.4±0.07 compared with 6.8±0.08 CD] and 5-HT [(pD2) 7.5±0.06 compared with 7.1±0.1 CD]. Vessels from rats on the HFD for 12 weeks and vessels treated with PugNAc displayed increased phosphorylation of p38 (Thr(180/182)) and extracellular signal-regulated kinase 1/2 (Erk1/2) (Ser(180/221)). Increased 5HT-induced contractions in arteries from rats on the HFD or in arteries incubated with PugNAc were abrogated by mitogen-activated protein kinase (MAPK) inhibitors. Our data show that HFD augments cerebrovascular O-GlcNAc and this modification contributes to increased contractile responses and to the activation of the MAPK pathway in the rat basilar artery.
authors.affiliation: Institute of Biological and Health Sciences, Federal University of Mato Grosso, Barra do Garças, MT, Brazil vvlima@ufmt.br.
authors.forename: Victor V
authors.initials: VV
authors.lastname: Lima
authors.affiliation: Institute of Biological and Health Sciences, Federal University of Mato Grosso, Barra do Garças, MT, Brazil.
authors.forename: Fernanda R
authors.initials: FR
authors.lastname: Giachini
authors.affiliation: Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Matsumoto
authors.affiliation: Department of Physiology, Augusta University, Augusta, GA, U.S.A.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Li
authors.affiliation: Institute of Biological and Health Sciences, Federal University of Mato Grosso, Barra do Garças, MT, Brazil.
authors.forename: Alecsander F M
authors.initials: AF
authors.lastname: Bressan
authors.affiliation: Department of Physiology, Augusta University, Augusta, GA, U.S.A.
authors.forename: Dhruv
authors.initials: D
authors.lastname: Chawla
authors.affiliation: Department of Physiology, Augusta University, Augusta, GA, U.S.A.
authors.forename: R Clinton
authors.initials: RC
authors.lastname: Webb
authors.affiliation: Department of Physiology, Augusta University, Augusta, GA, U.S.A.
authors.forename: Adviye
authors.initials: A
authors.lastname: Ergul
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto-SP, Brazil.
authors.forename: Rita C
authors.initials: RC
authors.lastname: Tostes
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism*; D000818:Animals; D002536:Cerebral Arteries / Q000378:metabolism*; D059305:Diet, High-Fat; D006949:Hyperlipidemias / Q000378:metabolism*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism; D009765:Obesity / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000502:physiology; D017208:Rats, Wistar; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism*
chemical_list: D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase; D020928:Mitogen-Activated Protein Kinases; C110628:hexosaminidase C; D001619:beta-N-Acetylhexosaminidases; D000117:Acetylglucosamine
keywords: O-GlcNAc; basilar artery; cerebral artery; high fat; vascular contraction