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Submitted on August 14, 2003
Accepted on June 1, 2004
Molecular Endocrinologyand Gene TranscriptionLaboratories, Baker Heart Research Institute, P.O. Box 6492 St. Kilda Road Central, Melbourne 8008, Australia; # Department of Biochemistry and Molecular Biology, Monash University, Melbourne 3800, Australia
* To whom correspondence should be addressed. E-mail: walter.thomas{at}baker.edu.au.
Urotensin-II and its receptor are co-expressed in the heart and up-regulated during cardiac dysfunction. In cultured neonatal cardiomyocytes, we mimicked this up-regulation using an adenovirus to increase expression of the urotensin receptor. In this model system, urotensin-II promoted strong hypertrophic growth and phenotypic changes, including cell enlargement and sarcomere re-organization. Urotensin-II potently activated the MAPKs, ERK1/2 and p38, and blocking these kinases with PD098059 and SB230580, respectively, significantly inhibited urotensin-II-mediated hypertrophy. In contrast, urotensin-II did not activate JNK. The activation of ERK1/2 and p38 as well as cellular hypertrophy was independent of protein kinase C, calcium and phosphoinositide 3-kinase, yet dependent on the capacity of the urotensin receptor to trans-activate the epidermal growth factor receptor. Urotensin-II promoted the tyrosine phosphorylation of epidermal growth factor receptors, which was inhibited by the selective epidermal growth factor receptor kinase inhibitor, AG1478. These data indicate that perturbations in cardiac homeostasis, which lead to up-regulation of urotensin-II receptors, promote urotensin-II-mediated cardiomyocyte hypertrophy via ERK1/2 and p38 signaling pathways in an epidermal growth factor receptor-dependent manner.
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