Inhibition of ErbB2 causes mitochondrial dysfunction in cardiomyocytes: implications for herceptin-induced cardiomyopathy

J Am Coll Cardiol. 2004 Dec 7;44(11):2231-8. doi: 10.1016/j.jacc.2004.08.066.


Objectives: We investigated the effects of erbB2 inhibition by anti-erbB2 antibody on cardiomyocyte survival and mitochondrial function.

Background: ErbB2 is an important signal integrator for the epidermal growth factor family of receptor tyrosine kinases. Herceptin, an inhibitory antibody to the erbB2 receptor, is a potent chemotherapeutic but causes cardiac toxicity.

Methods: Primary cultures of neonatal rat ventricular myocytes were exposed to anti-erbB2 antibody (Ab) (7.5 mug/ml) for up to 24 h. Cell viability, mitochondrial function, and apoptosis were measured using multiple complementary techniques.

Results: ErbB2 inhibition was associated with a dramatic increase in expression of the pro-apoptotic Bcl-2 family protein Bcl-xS and decreased levels of anti-apoptotic Bcl-xL. There was a time-dependent increase in mitochondrial translocation and oligomerization of bcl-associated protein (BAX), as indicated by 1,6-bismaleimidohexane crosslinking. The BAX oligomerization was associated with cytochrome c release and caspase activation. These alterations induced mitochondrial dysfunction, a loss of mitochondrial membrane potential (psi) (76.9 +/- 2.4 vs. 51.7 +/- 0.1; p < 0.05; n = 4), a 35% decline in adenosine triphosphate levels (p < 0.05), and a loss of redox capacity (0.72 +/- 0.04 vs. 0.64 +/- 0.02; p< 0.01). Restoration of Bcl-xL levels through transactivating regulatory protein-mediated protein transduction prevented the decline in psi mitochondrial reductase activity and cytosolic adenosine triphosphate.

Conclusions: Anti-erbB2 activates the mitochondrial apoptosis pathway through a previously undescribed modulation of Bcl-xL and -xS, causing impairment of mitochondrial function and integrity and disruption of cellular energetics.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Animals, Newborn
  • Antibodies, Monoclonal / pharmacology*
  • Antibodies, Monoclonal, Humanized
  • Apoptosis / physiology
  • Cell Fractionation
  • Cells, Cultured
  • Cross-Linking Reagents
  • Genes, erbB-2 / drug effects*
  • Genes, erbB-2 / physiology
  • In Situ Nick-End Labeling
  • Mitochondria, Heart / genetics
  • Mitochondria, Heart / physiology*
  • Myocytes, Cardiac / cytology*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Rats
  • Receptor, ErbB-2 / antagonists & inhibitors*
  • Transduction, Genetic
  • Trastuzumab
  • bcl-X Protein


  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Bcl2l1 protein, rat
  • Cross-Linking Reagents
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-X Protein
  • Receptor, ErbB-2
  • Trastuzumab