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J Am Coll Cardiol, 2004; 44:2231-2238, doi:10.1016/j.jacc.2004.08.066
© 2004 by the American College of Cardiology Foundation
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Inhibition of ErbB2 causes mitochondrial dysfunction in cardiomyocytes

Implications for herceptin-induced cardiomyopathy

Luanda P. Grazette, MD, MPH*,{dagger}, Wolfgang Boecker, MD*, Takashi Matsui, MD, PhD*,{dagger}, Marc Semigran, MD{dagger}, Thomas L. Force, MD{ddagger}, Roger J. Hajjar, MD*,{dagger} and Anthony Rosenzweig, MD*,{dagger},*

* Program in Cardiovascular Gene Therapy, Cardiovascular Research Center, Boston, Massachusetts
{dagger} Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
{ddagger} Tufts New England Medical Center, Boston, Massachusetts

Manuscript received January 28, 2004; revised manuscript received August 10, 2004, accepted August 23, 2004.

* Reprint requests and correspondence: Dr. Anthony Rosenzweig, Massachusetts General Hospital, 114 16th Street, Room 2600, Charlestown, Massachusetts 02129 (Email: arosenzweig{at}partners.org).

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 µg/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.

Abbreviations and Acronyms
  ARVM = adult rat ventricular myocytes
  ATP = adenosine triphosphate
  DNA = deoxyribonucleic acid
  EGF = epidermal growth factor
  MTT = mitochondrial reductase activity
  NRVM = neonatal rat ventricular cardiomyocytes
  PBS = phosphate-buffered saline
  RNA = ribonucleic acid
  TUNEL = terminal deoxynucleotidyl transferase dUTP nick end labeling
  Tyr = tyrosine




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