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Neuregulin receptors erbB2 and erbB4 in failing human myocardium -- depressed expression and attenuated activation

Susanne Rohrbach1, Bernd Niemann, Rolf-Edgar Silber

  • 1Institute of Pathophysiology, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06097 Halle, Germany. susanne.rohrbach@medizin.uni-halle.de

Basic Research in Cardiology
|February 3, 2005
PubMed

Insights

Heart failure reduces erbB receptor signaling, increasing pro-apoptotic Bcl-xS. This erbB receptor inactivation contributes to myocardial apoptosis in heart failure patients, even when neuregulin-1 levels are normal.

Area of Science:

  • Cardiovascular Biology
  • Molecular Cardiology
  • Cellular Signaling

Background:

  • Neuregulin (NRG) isoforms activate erbB tyrosine kinase receptors, influencing cell growth, survival, and differentiation.
  • In cardiomyocytes, erbB2 and erbB4 receptors modulate apoptosis via bcl-x splicing; erbB2 deficiency causes dilative cardiomyopathy.
  • Dysregulation of erbB signaling is implicated in heart failure pathogenesis.

Purpose of the Study:

  • To investigate the expression and activation status of erbB receptors in human heart failure.
  • To determine the impact of heart failure on erbB signaling pathways, including bcl-x splicing.
  • To explore the relationship between neuregulin levels and erbB receptor function in failing myocardium.

Main Methods:

  • Analysis of erbB receptor mRNA and protein expression in left ventricular myocardium from heart failure patients and organ donors.
  • Assessment of erbB receptor phosphorylation and bcl-x splicing patterns.
  • Quantification of neuregulin-1 isoform expression in failing and non-failing hearts.
  • Evaluation of erbB receptor expression before and after hemodynamic unloading with ventricular assist devices.

Main Results:

  • ErbB receptor mRNA and protein (erbB2: -25%; erbB4: -70%) are downregulated in failing myocardium, with mRNA levels normalizing after unloading.
  • Reduced erbB receptor phosphorylation and a shift in bcl-x splicing towards the pro-apoptotic Bcl-xS isoform were observed.
  • Neuregulin-1 isoforms, particularly in the endothelium, were induced in heart failure, with no evidence of inhibitory neuregulin isoforms.

Conclusions:

  • ErbB receptor inactivation, due to unknown mechanisms, contributes to increased myocardial apoptosis in heart failure.
  • Altered bcl-x splicing towards Bcl-xS formation enhances apoptotic susceptibility in failing human hearts.
  • The findings highlight a critical role for impaired erbB signaling in the pathophysiology of heart failure.

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