Inhibition of ErbB2 causes mitochondrial dysfunction in cardiomyocytes

  • Grazette L
  • Boecker W
  • Matsui T
  • et al.
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Abstract

OBJECTIVES<br />We investigated the effects of erbB2 inhibition by anti-erbB2 antibody on cardiomyocyte survival and mitochondrial function. <br /><br />BACKGROUND<br />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. <br /><br />METHODS<br />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. <br /><br />RESULTS<br />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 (ψ) (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 ψ mitochondrial reductase activity and cytosolic adenosine triphosphate. <br /><br />CONCLUSIONS<br />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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Grazette, L. P., Boecker, W., Matsui, T., Semigran, M., Force, T. L., Hajjar, R. J., & Rosenzweig, A. (2004). Inhibition of ErbB2 causes mitochondrial dysfunction in cardiomyocytes. Journal of the American College of Cardiology, 44(11), 2231–2238. https://doi.org/10.1016/j.jacc.2004.08.066

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