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


RESULTS
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
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.
Department of Molecular and Comparative Pathobiology, Johns Hopkins University, School of Medicine, Baltimore, Maryland, United States of America.
Polina
P
Sysa-Shah
Yi
Y
Xu
Xin
X
Guo
Frances
F
Belmonte
Byunghak
B
Kang
Djahida
D
Bedja
Scott
S
Pin
Noriko
N
Tsuchiya
Kathleen
K
Gabrielson
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000235:genetics; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D055724:Electrophysiological Phenomena; D015870:Gene Expression; D007545:Isoproterenol / Q000494:pharmacology; D000077341:Lapatinib; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology*; D009929:Organ Size / Q000187:drug effects; D009928:Organ Specificity; D014176:Protein Biosynthesis / Q000187:drug effects / Q000235:genetics; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*
D007545:Isoproterenol; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C483804:Erbb2 protein, rat