title: Cardiac O-GlcNAc signaling is increased in hypertrophy and heart failure.
abstract: Reversible protein O-GlcNAc modification has emerged as an essential intracellular signaling system in several tissues, including cardiovascular pathophysiology related to diabetes and acute ischemic stress. We tested the hypothesis that cardiac O-GlcNAc signaling is altered in chronic cardiac hypertrophy and failure of different etiologies. Global protein O-GlcNAcylation and the main enzymes regulating O-GlcNAc, O-GlcNAc transferase (OGT), O-GlcNAcase (OGA), and glutamine-fructose-6-phosphate amidotransferase (GFAT) were measured by immunoblot and/or real-time RT-PCR analyses of left ventricular tissue from aortic stenosis (AS) patients and rat models of hypertension, myocardial infarction (MI), and aortic banding (AB), with and without failure. We show here that global O-GlcNAcylation was increased by 65% in AS patients, by 47% in hypertensive rats, by 81 and 58% post-AB, and 37 and 60% post-MI in hypertrophic and failing hearts, respectively (P < 0.05). Noticeably, protein O-GlcNAcylation patterns varied in hypertrophic vs. failing hearts, and the most extensive O-GlcNAcylation was observed on proteins of 20-100 kDa in size. OGT, OGA, and GFAT2 protein and/or mRNA levels were increased by pressure overload, while neither was regulated by myocardial infarction. Pharmacological inhibition of OGA decreased cardiac contractility in post-MI failing hearts, demonstrating a possible role of O-GlcNAcylation in development of chronic cardiac dysfunction. Our data support the novel concept that O-GlcNAc signaling is altered in various etiologies of cardiac hypertrophy and failure, including human aortic stenosis. This not only provides an exciting basis for discovery of new mechanisms underlying pathological cardiac remodeling but also implies protein O-GlcNAcylation as a possible new therapeutic target in heart failure.
authors: Institute for Experimental Medical Research, Oslo University Hospital Ullevaal, Oslo, Norway. i.g.lunde@medisin.uio.no
authors: Ida G
authors: IG
authors: Lunde
authors: Jan Magnus
authors: JM
authors: Aronsen
authors: Heidi
authors: H
authors: Kvaløy
authors: Eirik
authors: E
authors: Qvigstad
authors: Ivar
authors: I
authors: Sjaastad
authors: Theis
authors: T
authors: Tønnessen
authors: Geir
authors: G
authors: Christensen
authors: Line M
authors: LM
authors: Grønning-Wang
authors: Cathrine R
authors: CR
authors: Carlson
mesh_terms: D000117:Acetylglucosamine / Q000502:physiology*; D000818:Animals; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) / Q000235:genetics / Q000378:metabolism; D006031:Glycosylation; D006333:Heart Failure / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D006984:Hypertrophy / Q000378:metabolism*; D009206:Myocardium / Q000201:enzymology* / Q000378:metabolism; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D015398:Signal Transduction; D001619:beta-N-Acetylhexosaminidases / Q000235:genetics / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing); C110628:hexosaminidase C; D001619:beta-N-Acetylhexosaminidases; D000117:Acetylglucosamine