Inhibition of ErbB2 causes mitochondrial dysfunction in cardiomyocytes
Implications for herceptin-induced cardiomyopathy
Luanda P. Grazette, MD, MPH*, ,
Wolfgang Boecker, MD*,
Takashi Matsui, MD, PhD*,,
Marc Semigran, MD,
Thomas L. Force, MD ,
Roger J. Hajjar, MD*, and
Anthony Rosenzweig, MD*,,*
* Program in Cardiovascular Gene Therapy, Cardiovascular Research Center, Boston, Massachusetts
Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
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 ( ) (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 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.
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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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