title: O-GlcNAcylation involvement in high glucose-induced cardiac hypertrophy via ERK1/2 and cyclin D2.
abstract: Continuous hyperglycemia is considered to be the most significant pathogenesis of diabetic cardiomyopathy, which manifests as cardiac hypertrophy and subsequent heart failure. O-GlcNAcylation has attracted attention as a post-translational protein modification in the past decade. The role of O-GlcNAcylation in high glucose-induced cardiomyocyte hypertrophy remains unclear. We studied the effect of O-GlcNAcylation on neonatal rat cardiomyocytes that were exposed to high glucose and myocardium in diabetic rats induced by streptozocin. High glucose (30 mM) incubation induced a greater than twofold increase in cell size and increased hypertrophy marker gene expression accompanied by elevated O-GlcNAcylation protein levels. High glucose increased ERK1/2 but not p38 MAPK or JNK activity, and cyclin D2 expression was also increased. PUGNAc, an inhibitor of β-N-acetylglucosaminidase, enhanced O-GlcNAcylation and imitated the effects of high glucose. OGT siRNA and ERK1/2 inhibition with PD98059 treatment blunted the hypertrophic response and cyclin D2 upregulation. OGT inhibition also prevented ERK1/2 activation. We also observed concentric hypertrophy and similar changes of O-GlcNAcylation level, ERK1/2 activation and cyclin D2 expression in myocardium of diabetic rats induced by streptozocin. In conclusion, O-GlcNAcylation plays a role in high glucose-induced cardiac hypertrophy via ERK1/2 and cyclin D2.
authors.affiliation: Department of Cardiology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Ding
authors.forename: Lu
authors.initials: L
authors.lastname: Yu
authors.forename: Meihui
authors.initials: M
authors.lastname: Wang
authors.forename: Shengjie
authors.initials: S
authors.lastname: Xu
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xia
authors.forename: Guosheng
authors.initials: G
authors.lastname: Fu
mesh_terms: D000117:Acetylglucosamine / Q000031:analogs & derivatives / Q000494:pharmacology; D000118:Acetylglucosaminidase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism*; D056742:Cyclin D2 / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D006031:Glycosylation; D006321:Heart / Q000187:drug effects; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D009206:Myocardium; D032383:Myocytes, Cardiac / Q000378:metabolism; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000378:metabolism*; D010091:Oximes / Q000494:pharmacology; D048448:Phenylcarbamates / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013311:Streptozocin; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D056742:Cyclin D2; D005419:Flavonoids; D010091:Oximes; D048448:Phenylcarbamates; D034741:RNA, Small Interfering; C068836:N-acetylglucosaminono-1,5-lactone O-(phenylcarbamoyl)oxime; D013311:Streptozocin; D017351:N-Acetylglucosaminyltransferases; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000118:Acetylglucosaminidase; D005947:Glucose; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D000117:Acetylglucosamine