RGD Reference Report - Non-canonical glycosyltransferase modulates post-hypoxic cardiac myocyte death and mitochondrial permeability transition. - Rat Genome Database

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Non-canonical glycosyltransferase modulates post-hypoxic cardiac myocyte death and mitochondrial permeability transition.

Authors: Ngoh, GA  Watson, LJ  Facundo, HT  Dillmann, W  Jones, SP 
Citation: Ngoh GA, etal., J Mol Cell Cardiol. 2008 Aug;45(2):313-25. doi: 10.1016/j.yjmcc.2008.04.009. Epub 2008 May 2.
RGD ID: 9590185
Pubmed: PMID:18539296   (View Abstract at PubMed)
PMCID: PMC2610867   (View Article at PubMed Central)
DOI: DOI:10.1016/j.yjmcc.2008.04.009   (Journal Full-text)

O-linked beta-N-acetylglucosamine (O-GlcNAc) is a dynamic, inducible, and reversible post-translational modification of nuclear and cytoplasmic proteins on Ser/Thr amino acid residues. In addition to its putative role as a nutrient sensor, we have recently shown pharmacologic elevation of O-GlcNAc levels positively affected myocyte survival during oxidant stress. However, no rigorous assessment of the contribution of O-GlcNAc transferase has been performed, particularly in the post-hypoxic setting. Therefore, we hypothesized that pharmacological or genetic manipulation of O-GlcNAc transferase (OGT), the enzyme that adds O-GlcNAc to proteins, would affect cardiac myocyte survival following hypoxia/reoxygenation (H/R). Adenoviral overexpression of OGT (AdOGT) in cardiac myocytes augmented O-GlcNAc levels and reduced post-hypoxic damage. Conversely, pharmacologic inhibition of OGT significantly attenuated O-GlcNAc levels, exacerbated post-hypoxic cardiac myocyte death, and sensitized myocytes to mitochondrial membrane potential collapse. Both genetic deletion of OGT using a cre-lox approach and translational silencing via RNAi also resulted in significant reductions in OGT protein and O-GlcNAc levels, and, exacerbated post-hypoxic cardiac myocyte death. Inhibition of OGT reduced O-GlcNAc levels on voltage dependent anion channel (VDAC) in isolated mitochondria and sensitized to calcium-induced mitochondrial permeability transition pore (mPTP) formation, indicating that mPTP may be an important target of O-GlcNAc signaling and confirming the aforementioned mitochondrial membrane potential results. These data demonstrate that OGT exerts pro-survival actions during hypoxia-reoxygenation in cardiac myocytes, particularly at the level of mitochondria.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
OgtRatglucosamine metabolic process  IMP  RGD 
OgtRatnegative regulation of cellular response to hypoxia  IMP cell deathRGD 

Objects Annotated

Genes (Rattus norvegicus)
Ogt  (O-linked N-acetylglucosamine (GlcNAc) transferase)


Additional Information