Cardiac-specific over-expression of epidermal growth factor receptor 2 (ErbB2) induces pro-survival pathways and hypertrophic cardiomyopathy in mice

Polina Sysa-Shah, Yi Xu, Xin Guo, Frances Belmonte, Byunghak Kang, Djahida Bedja, Scott Pin, Noriko Tsuchiya, Kathleen L Gabrielson

Research output: Contribution to journalArticle

Abstract

Background: Emerging evidence shows that ErbB2 signaling has a critical role in cardiomyocyte physiology, based mainly on findings that blocking ErbB2 for cancer therapy is toxic to cardiac cells. However, consequences of high levels of ErbB2 activity in the heart have not been previously explored. Methodology/Principal Findings: We investigated consequences of cardiac-restricted over-expression of ErbB2 in two novel lines of transgenic mice. Both lines develop striking concentric cardiac hypertrophy, without heart failure or decreased life span. ErbB2 transgenic mice display electrocardiographic characteristics similar to those found in patients with Hypertrophic Cardiomyopathy, with susceptibility to adrenergic-induced arrhythmias. The hypertrophic hearts, which are 2-3 times larger than those of control littermates, express increased atrial natriuretic peptide and β-myosin heavy chain mRNA, consistent with a hypertrophic phenotype. Cardiomyocytes in these hearts are significantly larger than wild type cardiomyocytes, with enlarged nuclei and distinctive myocardial disarray. Interestingly, the over-expression of ErbB2 induces a concurrent up-regulation of multiple proteins associated with this signaling pathway, including EGFR, ErbB3, ErbB4, PI3K subunits p110 and p85, bcl-2 and multiple protective heat shock proteins. Additionally, ErbB2 up-regulation leads to an anti-apoptotic shift in the ratio of bcl-xS/xL in the heart. Finally, ErbB2 over-expression results in increased activation of the translation machinery involving S6, 4E-BP1 and eIF4E. The dependence of this hypertrophic phenotype on ErbB family signaling is confirmed by reduction in heart mass and cardiomyocyte size, and inactivation of pro-hypertrophic signaling in transgenic animals treated with the ErbB1/2 inhibitor, lapatinib. Conclusions/Significance: These studies are the first to demonstrate that increased ErbB2 over-expression in the heart can activate protective signaling pathways and induce a phenotype consistent with Hypertrophic Cardiomyopathy. Furthermore, our work suggests that in the situation where ErbB2 signaling contributes to cardiac hypertrophy, inhibition of this pathway may reverse this process.

Original languageEnglish (US)
Article numbere42805
JournalPLoS One
Volume7
Issue number8
DOIs
StatePublished - Aug 9 2012

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Hypertrophic Cardiomyopathy
cardiomyopathy
Epidermal Growth Factor Receptor
heart
Cardiac Myocytes
Survival
mice
Cardiomegaly
Phenotype
hypertrophy
phenotype
Transgenic Mice
Up-Regulation
genetically modified organisms
S 6
atrial natriuretic peptide
transgenic animals
Genetically Modified Animals
Myosin Heavy Chains
myosin heavy chains

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Cardiac-specific over-expression of epidermal growth factor receptor 2 (ErbB2) induces pro-survival pathways and hypertrophic cardiomyopathy in mice. / Sysa-Shah, Polina; Xu, Yi; Guo, Xin; Belmonte, Frances; Kang, Byunghak; Bedja, Djahida; Pin, Scott; Tsuchiya, Noriko; Gabrielson, Kathleen L.

In: PLoS One, Vol. 7, No. 8, e42805, 09.08.2012.

Research output: Contribution to journalArticle

Sysa-Shah, Polina ; Xu, Yi ; Guo, Xin ; Belmonte, Frances ; Kang, Byunghak ; Bedja, Djahida ; Pin, Scott ; Tsuchiya, Noriko ; Gabrielson, Kathleen L. / Cardiac-specific over-expression of epidermal growth factor receptor 2 (ErbB2) induces pro-survival pathways and hypertrophic cardiomyopathy in mice. In: PLoS One. 2012 ; Vol. 7, No. 8.
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AU - Sysa-Shah, Polina

AU - Xu, Yi

AU - Guo, Xin

AU - Belmonte, Frances

AU - Kang, Byunghak

AU - Bedja, Djahida

AU - Pin, Scott

AU - Tsuchiya, Noriko

AU - Gabrielson, Kathleen L

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