ErbB2 is essential in the prevention of dilated cardiomyopathy

Steven A. Crone; You Yang Zhao; Lian Fan; Yusu Gu; Susumu Minamisawa; Yang Liu; Kirk L. Peterson; Ju Chen; Ronald Kahn; Gianluigi Condorelli; John Ross; Kenneth R. Chien; Kuo Fen Lee

doi:10.1038/nm0502-459

ErbB2 is essential in the prevention of dilated cardiomyopathy

Steven A. Crone, You Yang Zhao, Lian Fan, Yusu Gu, Susumu Minamisawa, Yang Liu, Kirk L. Peterson, Ju Chen, Ronald Kahn, Gianluigi Condorelli, John Ross, Kenneth R. Chien, Kuo Fen Lee

Pediatrics

Research output: Contribution to journal › Article › peer-review

734 Scopus citations

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.

Original language	English (US)
Pages (from-to)	459-465
Number of pages	7
Journal	Nature Medicine
Volume	8
Issue number	5
DOIs	https://doi.org/10.1038/nm0502-459
State	Published - 2002

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/nm0502-459

Cite this

@article{9025a0d107764982aed5980706951915,

title = "ErbB2 is essential in the prevention of dilated cardiomyopathy",

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.",

author = "Crone, {Steven A.} and Zhao, {You Yang} and Lian Fan and Yusu Gu and Susumu Minamisawa and Yang Liu and Peterson, {Kirk L.} and Ju Chen and Ronald Kahn and Gianluigi Condorelli and John Ross and Chien, {Kenneth R.} and Lee, {Kuo Fen}",

note = "Funding Information: Acknowledgments 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.",

year = "2002",

doi = "10.1038/nm0502-459",

language = "English (US)",

volume = "8",

pages = "459--465",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "Nature Publishing Group",

number = "5",

}

TY - JOUR

T1 - ErbB2 is essential in the prevention of dilated cardiomyopathy

AU - Crone, Steven A.

AU - Zhao, You Yang

AU - Fan, Lian

AU - Gu, Yusu

AU - Minamisawa, Susumu

AU - Liu, Yang

AU - Peterson, Kirk L.

AU - Chen, Ju

AU - Kahn, Ronald

AU - Condorelli, Gianluigi

AU - Ross, John

AU - Chien, Kenneth R.

AU - Lee, Kuo Fen

N1 - Funding Information: Acknowledgments 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.

PY - 2002

Y1 - 2002

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0036099675&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036099675&partnerID=8YFLogxK

U2 - 10.1038/nm0502-459

DO - 10.1038/nm0502-459

M3 - Article

C2 - 11984589

AN - SCOPUS:0036099675

SN - 1078-8956

VL - 8

SP - 459

EP - 465

JO - Nature Medicine

JF - Nature Medicine

IS - 5

ER -

ErbB2 is essential in the prevention of dilated cardiomyopathy

Abstract

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this