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ErbB2 is essential in the prevention of dilated cardiomyopathy

Nature Medicine volume 8, pages 459–465 (2002)Cite this article

Abstract

Amplification of the gene encoding the ErbB2 (Her2/neu) receptor tyrosine kinase is critical for the progression of several forms of breast cancer. In a large-scale clinical trial, treatment with Herceptin (trastuzumab), a humanized blocking antibody against ErbB2, led to marked improvement in survival. However, cardiomyopathy was uncovered as a mitigating side effect, thereby suggesting an important role for ErbB2 signaling as a modifier of human heart failure. To investigate the physiological role of ErbB2 signaling in the adult heart, we generated mice with a ventricular-restricted deletion of Erbb2. These ErbB2-deficient conditional mutant mice were viable and displayed no overt phenotype. However, physiological analysis revealed the onset of multiple independent parameters of dilated cardiomyopathy, including chamber dilation, wall thinning and decreased contractility. Additionally, cardiomyocytes isolated from these conditional mutants were more susceptible to anthracycline toxicity. ErbB2 signaling in cardiomyocytes is therefore essential for the prevention of dilated cardiomyopathy.

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Figure 1: Ventricular chamber-restricted deletion of Erbb2.
Figure 2: Phenotypic analyses of Erbb2-CKO mice.
Figure 3: Erbb2-CKO mice display normal responses to dobutamine treatment and decreased survival following pressure overload.
Figure 4: Prevention of dilated cardiomyopathy in Erbb2-CKO mice by overexpression of Bcl-xL.
Figure 5: Cardiomyocytes from Erbb2-CKO mice are more sensitive to adriamycin-induced cell death.

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Acknowledgements

We thank K. Campbell and Y. Kobayashi for antibodies against cytoskeletal proteins; R. Gottlieb and R. Sayen for analysis of the function of mitochondria; J. Adams for adenoviral Bcl-xL; Ma. Hoshijima for help with adenovirus injection; and N. Dalton for expertise in echocardiography. The work was supported by NIH grants and The Jean Le Ducq Foundation (to K.R.C. and K.F.L.) and support from an AHA endowed chair and Genentech, Inc (to K.R.C.). S.A.C. is a Markey Predoctoral Fellow and recipient of an award from the Chapman Foundation. K.F.L. is a Pew Scholar.

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Author notes

  1. Steven A. Crone and You-Yang Zhao: S.A.C. and Y.-Y.Z. contributed equally to this study.

Authors and Affiliations

  1. The Salk Institute, La Jolla, California, USA

    Steven A. Crone & Kuo-Fen Lee

  2. UCSD-Salk Program in Molecular Medicine, University of California at San Diego, La Jolla, California, USA

    Steven A. Crone, You-Yang Zhao, Yusu Gu, Susumu Minamisawa, Yang Liu, Kirk L. Peterson, Ju Chen, John Ross Jr, Kenneth R. Chien & Kuo-Fen Lee

  3. Division of Biology, University of California at San Diego, La Jolla, California, USA

    Steven A. Crone

  4. The Institute of Molecular Medicine, University of California at San Diego, La Jolla, California, USA

    You-Yang Zhao, Yusu Gu, Susumu Minamisawa, Yang Liu, Kirk L. Peterson, Ju Chen, John Ross Jr & Kenneth R. Chien

  5. Department of Immunology, The Scripps Research Institute, La Jolla, California, USA

    Lian Fan

  6. Research Division, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA

    Ronald Kahn

  7. Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA

    Gianluigi Condorelli

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Correspondence to Kuo-Fen Lee.

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Competing interests

K.R.C. is a consultant to Genentech in the area of heart failure and cardiomyopathy.

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Crone, S., Zhao, YY., Fan, L. et al. ErbB2 is essential in the prevention of dilated cardiomyopathy. Nat Med 8, 459–465 (2002). https://doi.org/10.1038/nm0502-459

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