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Cardiac transcription factor Nkx2.5 is downregulated under excessive O-GlcNAcylation condition

Hoe Suk Kim1, Ji Soo Woo, Hyun Jung Joo

  • 1The Institute of Radiation Medicine, Medical Research Center, Seoul National University, Jongno-gu, Seoul, Korea.

Plos One
|June 22, 2012
PubMed

Insights

Excessive O-linked N-acetylglucosamine (O-GlcNAc) modification of Nkx2.5 protein reduces its levels, contributing to diabetic cardiomyopathy development.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cardiovascular Research

Background:

  • Diabetic cardiomyopathy is linked to O-linked N-acetylglucosamine (O-GlcNAc) protein modification.
  • Nkx2.5 is a crucial cardiac transcription factor implicated in heart development and function.

Purpose of the Study:

  • To investigate the regulatory role of O-GlcNAc modification on Nkx2.5 protein.
  • To determine if Nkx2.5 is a direct target of O-GlcNAc transferase (OGT) and O-GlcNAcase (OGC).

Main Methods:

  • Recombinant Nkx2.5 protein was treated with O-GlcNAcase inhibitors (STZ, PUGNAC) and OGT overexpression.
  • Co-immunoprecipitation assays were used to detect interactions between Nkx2.5 and OGT.
  • Nkx2.5 modification by O-GlcNAc was assessed in vitro and in vivo using diabetic mouse models.

Main Results:

  • O-GlcNAc modification reduced recombinant Nkx2.5 protein levels.
  • Nkx2.5 directly interacted with OGT, indicating O-GlcNAc modification.
  • Nkx2.5 protein levels were decreased, while O-GlcNAc modification was increased in the hearts of diabetic mice.

Conclusions:

  • Excessive O-GlcNAcylation leads to Nkx2.5 downregulation.
  • Nkx2.5 downregulation by O-GlcNAc modification is a potential mechanism contributing to diabetic cardiomyopathy.

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