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The Ku protein complex interacts with YY1, is up-regulated in human heart failure, and represses alpha myosin

Carmen C Sucharov1, Steve M Helmke, Stephen J Langer

  • 1Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, USA.

Molecular and Cellular Biology
|September 16, 2004
PubMed

Insights

Ku70/80 protein levels increase in heart failure, repressing alpha myosin heavy chain (alphaMyHC) gene expression. This protein complex, along with YY1, contributes to reduced heart contractility in heart failure.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Biochemistry

Background:

  • Heart failure is characterized by altered gene expression, including repression of alpha myosin heavy chain (alphaMyHC) and induction of fetal genes.
  • Changes in myosin heavy chain (MyHC) isoforms significantly impact cardiac myocyte contractility and overall heart function.
  • Previous research indicated increased YY1 protein levels in human heart failure, with YY1 shown to repress the alphaMyHC promoter.

Purpose of the Study:

  • To identify factors that bind to the alphaMyHC promoter and are upregulated in failing human hearts.
  • To investigate the role of Ku70/80 in the repression of the alphaMyHC promoter during heart failure.
  • To explore the interaction between YY1 and Ku70/80 in regulating alphaMyHC expression.

Main Methods:

  • Identification of a DNA-binding factor in the alphaMyHC promoter using peptide mass spectrometry.
  • Expression analysis of Ku70/80 in failing human hearts.
  • In vitro studies using neonatal rat ventricular myocytes to assess the effect of Ku expression on alphaMyHC promoter activity.
  • Co-immunoprecipitation assays to determine the interaction between YY1, Ku70, and Ku80.

Main Results:

  • A specific region of the alphaMyHC promoter was found to bind a factor whose expression increased sixfold in failing human hearts.
  • Peptide mass spectrometry identified this factor as a heterodimer of Ku70 and Ku80.
  • Ku expression repressed the human alphaMyHC promoter in neonatal rat ventricular myocytes.
  • Overexpression of Ku70/80 decreased alphaMyHC mRNA levels and increased skeletal alpha-actin expression.
  • YY1 was found to interact with Ku70 and Ku80, and the combined presence of YY1, Ku70, and Ku80 resulted in greater repression of the alphaMyHC promoter than either factor alone.

Conclusions:

  • Ku70/80 is a significant factor involved in the repression of the human alphaMyHC promoter in the context of heart failure.
  • The synergistic repression of the alphaMyHC promoter by YY1 and Ku70/80 highlights a novel molecular mechanism in heart failure pathophysiology.
  • These findings identify Ku as a potential therapeutic target for heart failure by modulating alphaMyHC gene expression.

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