Nature Medicine
8, 459 - 465 (2002)
doi:10.1038/nm0502-459
ErbB2 is essential in the prevention of dilated cardiomyopathySteven A. Crone1, 2, 3, 8, You-Yang Zhao2, 4, 8, Lian Fan5, Yusu Gu2, 4, Susumu Minamisawa2, 4, Yang Liu2, 4, Kirk L. Peterson2, 4, Ju Chen2, 4, Ronald Kahn6, Gianluigi Condorelli7, John Ross Jr2, 4, Kenneth R. Chien2, 4
& Kuo-Fen Lee1, 21
The Salk Institute, La Jolla, California, USA
2
UCSD-Salk Program in Molecular Medicine, University of California at San Diego, La Jolla, California, USA
3
Division of Biology, University of California at San Diego, La Jolla, California, USA
4
The Institute of Molecular Medicine, University of California at San Diego, La Jolla, California, USA
5
Department of Immunology, The Scripps Research Institute, La Jolla, California, USA
6
Research Division, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
7
Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
8
S.A.C. and Y.-Y.Z. contributed equally to this study.
Correspondence should be addressed to Kuo-Fen Lee klee@salk.eduAmplification 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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