cAMP-response element-binding protein mediates prostaglandin F2alpha-induced hypertrophy of vascular smooth muscle cells

Prostaglandin F(2alpha) (PGF(2alpha)) is a vasoactive factor that causes constriction and hypertrophy of vascular smooth muscle cells (VSMCs). However, the mechanism of PGF(2alpha)-induced hypertrophy is largely unknown. Cyclic AMP-response element (CRE)-binding protein (CREB), the best characterize...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 2005-12, Vol.338 (2), p.910-918
Main Authors: Fukuyama, Kae, Ichiki, Toshihiro, Ono, Hiroki, Tokunou, Tomotake, Iino, Naoko, Masuda, Satoko, Ohtsubo, Hideki, Takeshita, Akira
Format: Article
Language:English
Subjects:
Animals
Cells, Cultured
CREB-Binding Protein - metabolism
Dinoprost - administration & dosage
Dose-Response Relationship, Drug
Hypertrophy - chemically induced
Hypertrophy - metabolism
Hypertrophy - pathology
Muscle, Smooth, Vascular - drug effects
Muscle, Smooth, Vascular - metabolism
Muscle, Smooth, Vascular - pathology
Myocytes, Smooth Muscle - drug effects
Myocytes, Smooth Muscle - metabolism
Myocytes, Smooth Muscle - pathology
Rats
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Summary:Prostaglandin F(2alpha) (PGF(2alpha)) is a vasoactive factor that causes constriction and hypertrophy of vascular smooth muscle cells (VSMCs). However, the mechanism of PGF(2alpha)-induced hypertrophy is largely unknown. Cyclic AMP-response element (CRE)-binding protein (CREB), the best characterized stimulus-induced transcription factor, activates transcription of target genes with CRE and promotes cell growth. We examined the role of CREB in PGF(2alpha)-induced hypertrophy of VSMCs. PGF(2alpha) induced phosphorylation of CREB at serine 133, which is a critical marker of activation, after 5-10min of stimulation in a dose-dependent manner. Pharmacological inhibition of extracellular signal-regulated protein kinase and p38 mitogen-activated protein kinase (p38-MAPK) suppressed PGF(2alpha)-induced CREB phosphorylation. Inhibition of epidermal growth factor receptor (EGFR) and mitogen- and stress-activated protein kinase-1 also suppressed PGF(2alpha)-induced CREB phosphorylation. Overexpression of dominant-negative form of CREB (AdCREB M1), of which serine 133 was replaced with alanine, inhibited PGF(2alpha)-induced c-fos mRNA expression as well as hypertrophy of VSMCs [hypertrophy index (microg/10(4)cell); control 8.13, PGF(2alpha) 9.85, AdCREB M1 7.91, and AdCREB M1+PGF(2alpha) 8.43]. These results suggest that PGF(2alpha) activated CRE-dependent gene transcription through EGFR transactivation, and the CREB pathway plays a critical role in PGF(2alpha)-induced hypertrophy of VSMCs.
ISSN:0006-291X