Effect of dominant-negative epidermal growth factor receptors on cardiomyocyte hypertrophy.
Angiotensin II (AngII) induces heart growth via cardiomyocyte hypertrophy, and central to this is the capacity of the type 1 AngII receptor (AT1R) to "transactivate" epidermal growth factor receptors (EGFRs)--a family with four main subtypes (HER1-4)--although the exact molecular mechanism remains unresolved. In this study, the pharmacological inhibition of AngII-stimulated ERK1/2 activation and cardiomyocyte hypertrophy by increasing concentrations of an EGFR inhibitor, AG1478, indicated that other EGFR subtypes, in addition to HER1, may be involved. We constructed expression vectors and adenoviruses expressing truncated mutant versions of HER1, HER2, and HER4 and determined their capacity to act as dominant-negative inhibitors when co-transfected with full-length EGFRs. It is surprising that adenoviral-mediated expression of these truncated EGFRs in cardiomyocytes led to paradoxical, ligand-independent increases in cardiomyocyte hypertrophy and unusual morphological changes. These results challenge our perception of AT1R-mediated EGFR transactivation and imply that truncated EGFRs may affect cell function through unconventional mechanisms.
Chan
Hsiu-Wen
HW
Molecular Endocrinology Laboratory, Baker Heart Research Institute, Prahran, Melbourne, Victoria, Australia.
Jenkins
Anna
A
Pipolo
Luisa
L
Hannan
Ross D
RD
Thomas
Walter G
WG
Smith
Nicola J
NJ
D000804:Angiotensin II / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000235:genetics* / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D006984:Hypertrophy / Q000209:etiology*; D032383:Myocytes, Cardiac / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000502:physiology; D020893:Receptor, ErbB-3 / Q000502:physiology; D066247:Receptor, ErbB-4
D000804:Angiotensin II; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4; C512478:EGFR protein, human; C587689:ERBB4 protein, human; C587691:Erbb4 protein, rat