ErbB2 is essential in the prevention of dilated cardiomyopathy.
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.
Crone
Steven A
SA
The Salk Institute, La Jolla, California, USA.
Zhao
You-Yang
YY
Fan
Lian
L
Gu
Yusu
Y
Minamisawa
Susumu
S
Liu
Yang
Y
Peterson
Kirk L
KL
Chen
Ju
J
Kahn
Ronald
R
Condorelli
Gianluigi
G
Ross
John
J
Chien
Kenneth R
KR
Lee
Kuo-Fee
KF
D000328:Adult; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000517:prevention & control; D004317:Doxorubicin / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D005784:Gene Amplification; D020043:Genes, Essential; D018734:Genes, erbB-2; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006339:Heart Rate; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D066247:Receptor, ErbB-4; D015398:Signal Transduction
D004317:Doxorubicin; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; D066247:Receptor, ErbB-4; C587689:ERBB4 protein, human; C587690:Erbb4 protein, mouse