title: Cardiomyocyte Ogt limits ventricular dysfunction in mice following pressure overload without affecting hypertrophy.
abstract: The myocardial response to pressure overload involves coordination of multiple transcriptional, posttranscriptional, and metabolic cues. The previous studies show that one such metabolic cue, O-GlcNAc, is elevated in the pressure-overloaded heart, and the increase in O-GlcNAcylation is required for cardiomyocyte hypertrophy in vitro. Yet, it is not clear whether and how O-GlcNAcylation participates in the hypertrophic response in vivo. Here, we addressed this question using patient samples and a preclinical model of heart failure. Protein O-GlcNAcylation levels were increased in myocardial tissue from heart failure patients compared with normal patients. To test the role of OGT in the heart, we subjected cardiomyocyte-specific, inducibly deficient Ogt (i-cmOgt-/-) mice and Ogt competent littermate wild-type (WT) mice to transverse aortic constriction. Deletion of cardiomyocyte Ogt significantly decreased O-GlcNAcylation and exacerbated ventricular dysfunction, without producing widespread changes in metabolic transcripts. Although some changes in hypertrophic and fibrotic signaling were noted, there were no histological differences in hypertrophy or fibrosis. We next determined whether significant differences were present in i-cmOgt-/-cardiomyocytes from surgically naïve mice. Interestingly, markers of cardiomyocyte dedifferentiation were elevated in Ogt-deficient cardiomyocytes. Although no significant differences in cardiac dysfunction were apparent after recombination, it is possible that such changes in dedifferentiation markers could reflect a larger phenotypic shift within the Ogt-deficient cardiomyocytes. We conclude that cardiomyocyte Ogt is not required for cardiomyocyte hypertrophy in vivo; however, loss of Ogt may exert subtle phenotypic differences in cardiomyocytes that sensitize the heart to pressure overload-induced ventricular dysfunction.
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Institute of Molecular Cardiology, Diabetes and Obesity Center, University of Louisville, 580 South Preston Street, Louisville, KY, 40202, USA.
authors.forename: Sujith
authors.initials: S
authors.lastname: Dassanayaka
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Institute of Molecular Cardiology, Diabetes and Obesity Center, University of Louisville, 580 South Preston Street, Louisville, KY, 40202, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Brainard
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Institute of Molecular Cardiology, Diabetes and Obesity Center, University of Louisville, 580 South Preston Street, Louisville, KY, 40202, USA.|Kentucky College of Osteopathic Medicine, University of Pikeville, Pikeville, KY, USA.
authors.forename: Lewis J
authors.initials: LJ
authors.lastname: Watson
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Institute of Molecular Cardiology, Diabetes and Obesity Center, University of Louisville, 580 South Preston Street, Louisville, KY, 40202, USA.
authors.forename: Bethany W
authors.initials: BW
authors.lastname: Long
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Institute of Molecular Cardiology, Diabetes and Obesity Center, University of Louisville, 580 South Preston Street, Louisville, KY, 40202, USA.
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Brittian
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Institute of Molecular Cardiology, Diabetes and Obesity Center, University of Louisville, 580 South Preston Street, Louisville, KY, 40202, USA.
authors.forename: Angelica M
authors.initials: AM
authors.lastname: DeMartino
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Institute of Molecular Cardiology, Diabetes and Obesity Center, University of Louisville, 580 South Preston Street, Louisville, KY, 40202, USA.
authors.forename: Allison L
authors.initials: AL
authors.lastname: Aird
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Institute of Molecular Cardiology, Diabetes and Obesity Center, University of Louisville, 580 South Preston Street, Louisville, KY, 40202, USA.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Gumpert
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Institute of Molecular Cardiology, Diabetes and Obesity Center, University of Louisville, 580 South Preston Street, Louisville, KY, 40202, USA.
authors.forename: Timothy N
authors.initials: TN
authors.lastname: Audam
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Institute of Molecular Cardiology, Diabetes and Obesity Center, University of Louisville, 580 South Preston Street, Louisville, KY, 40202, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Kilfoil
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Institute of Molecular Cardiology, Diabetes and Obesity Center, University of Louisville, 580 South Preston Street, Louisville, KY, 40202, USA.
authors.forename: Senthilkumar
authors.initials: S
authors.lastname: Muthusamy
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Institute of Molecular Cardiology, Diabetes and Obesity Center, University of Louisville, 580 South Preston Street, Louisville, KY, 40202, USA.|Division of Cardiovascular Disease and Comprehensive Cardiovascular Center, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Tariq
authors.initials: T
authors.lastname: Hamid
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Institute of Molecular Cardiology, Diabetes and Obesity Center, University of Louisville, 580 South Preston Street, Louisville, KY, 40202, USA.|Division of Cardiovascular Disease and Comprehensive Cardiovascular Center, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Sumanth D
authors.initials: SD
authors.lastname: Prabhu
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Institute of Molecular Cardiology, Diabetes and Obesity Center, University of Louisville, 580 South Preston Street, Louisville, KY, 40202, USA. Steven.P.Jones@Louisville.edu.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Jones
mesh_terms: D000818:Animals; D017209:Apoptosis; D006332:Cardiomegaly / Q000378:metabolism*; D004195:Disease Models, Animal; D006333:Heart Failure / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000378:metabolism*; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism*; D016133:Polymerase Chain Reaction
chemical_list: D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase
keywords: Glycosylation; Heart failure; Hexosamine biosynthetic pathway; Metabolism