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Cardiomyocyte Ogt limits ventricular dysfunction in mice following pressure overload without affecting hypertrophy
Author(s) -
Dassanayaka Sujith,
Brainard Robert E,
Watson Lewis J,
Long Bethany W,
Brittian Kenneth R,
DeMartino Angelica M,
Aird Allison L,
Kilfoil Peter J,
Muthusamy Senthilkumar,
Hamid Tariq,
Prabhu Sumanth D,
Jones Steven P
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1273.2
Subject(s) - pressure overload , muscle hypertrophy , heart failure , fibrosis , in vivo , medicine , cardiac hypertrophy , left ventricular hypertrophy , biology , endocrinology , phenotype , cardiology , microbiology and biotechnology , blood pressure , biochemistry , gene , genetics
The myocardial response to pressure overload involves coordination of multiple transcriptional, posttranscriptional, and metabolic cues. Previous studies show that one such metabolic cue, O‐linked beta‐N‐acetylglucosamine (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 O‐GlcNAc transferase (OGT) in the heart, we subjected cardiomyocyte‐specific, inducibly deficient Ogt (i‐cm Ogt −/− ) mice and Ogt competent littermate wild type (WT) mice to transverse aortic constriction (TAC). Deletion of cardiomyocyte Ogt significantly decreased O‐GlcNAcylation and exacerbated ventricular dysfunction, without producing widespread changes in metabolic transcripts. Although some changes in hypertrophic (elevated Nppa , reduction in GATA4) and fibrotic signaling (elevated Tgfb2 , reduction in Fgf2 ) were noted, there were no histological differences in hypertrophy or fibrosis. We next determined whether significant differences were present in i‐cm Ogt −/− cardiomyocytes from surgically‐naïve mice. Interestingly, markers of cardiomyocyte dedifferentiation ( Acta2 , Nkx 2–5 ) 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. Because diabetes is often associated with altered O‐GlcNAcylation, our findings could have implications for the diabetic heart. Support or Funding Information Dr. Jones has been supported by grants from the NIH (R01 HL083320, R01 HL094419, P20 RR103492, and P01 HL078825). Mr. Dassanayaka holds an American Heart Association Predoctoral Fellowship – Great Rivers Affiliate (14PRE19710015).