Premium
Cardiomyocyte Ogt is essential for maintaining cardiac function (1078.1)
Author(s) -
DeMartino Angelica,
Watson Lewis,
Long Bethany,
Brittian Kenneth,
Readnower Ryan,
Brainard Robert,
Cummins Timothy,
Annamalai Lakshmanan,
Hill Bradford,
Jones Steven
Publication year - 2014
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.28.1_supplement.1078.1
Subject(s) - heart failure , cardiomyopathy , endoplasmic reticulum , cardiac function curve , unfolded protein response , transgene , medicine , genetically modified mouse , endocrinology , cardiac fibrosis , cardioprotection , cardiology , biology , microbiology and biotechnology , myocardial infarction , biochemistry , gene
O‐GlcNAc transferase (OGT) catalyzes the post‐translational protein modification, O‐GlcNAc, in response to acute stress. We previously demonstrated a role for O‐GlcNAc in acute cardioprotection and heart failure; however, its roles in the developing heart and in the adult, non‐infarcted heart remain unknown. We hypothesized that constitutive, cardiomyocyte‐specific OGT ablation (c‐cmOGT KO) would impair cardiac function as the heart transitioned from a low afterload in utero to high as a neonate. Indeed, c‐cmOGT KO mice had impaired survival, were runted compared to littermates, had cardiomegaly, displayed marked cardiac fibrosis, and had dramatically depressed ventricular function. Histology revealed pathology in the endoplasmic reticulum (ER) and immunoblotting indicated ER stress (Grp78 and PDI) in c‐cmOGT KO hearts. Heterozygous OGT deficient mice were also generated and, unlike the acute, severe heart failure observed in the c‐cmOGT KO, heterozygous mice experienced a progressive cardiomyopathy, suggesting a potential dose‐dependent effect. Finally, we inducibly‐deleted cardiomyocyte OGT via the MerCreMer transgene. Although there were no significant defects apparent within the first few weeks, ventricular function significantly and progressively declined several weeks following deletion. These results indicate a critical, yet dynamic, role for OGT in developing and mature hearts. Grant Funding Source : Supported by the NIH and AHA