Urotensin II promotes hypertrophy of cardiac myocytes via mitogen-activated protein kinases.
Urotensin II and its receptor are coexpressed 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 reorganization. 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, and 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.
Onan
Döne
D
Molecular Endocrinology, Baker Heart Research Institute, P.O. Box 6492, St. Kilda Road Central, Melbourne 8008, Victoria, Australia.
Pipolo
Luisa
L
Yang
Eunice
E
Hannan
Ross D
RD
Thomas
Walter G
WG
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049108:Cell Enlargement; D002478:Cells, Cultured; D003001:Cloning, Molecular; D066246:ErbB Receptors; D005822:Genetic Vectors / Q000235:genetics; D006023:Glycoproteins / Q000235:genetics / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation / Q000235:genetics; D015854:Up-Regulation; D014579:Urotensins / Q000494:pharmacology*
D006023:Glycoproteins; D043562:Receptors, G-Protein-Coupled; D014579:Urotensins; C473142:Uts2r protein, rat; C029677:urotensin II; C483803:Egfr protein, rat; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases