on July 8, 2004
Published online before print July 8, 2004, doi: 10.1161/01.ATV.0000138052.86051.0d
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Submitted on February 27, 2004
Accepted on June 25, 2004
cAMP-Response Element-Binding Protein Mediates Tumor Necrosis Factor-
-Induced Vascular Smooth Muscle Cell Migration
Hiroki Ono ;
From the Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
* To whom correspondence should be addressed. E-mail: ichiki{at}cardiol.med.kyushu-u.ac.jp.
Objective--Migration of vascular smooth muscle cells (VSMCs) contributes to formation of vascular stenotic lesions such as atherosclerosis and restenosis after angioplasty. Previous studies have demonstrated that tumor necrosis factor-
(TNF-) is a potent migration factor for VSMCs. cAMP-response element-binding protein (CREB) is the stimulus-induced transcription factor and activates transcription of target genes such as c-fos and interleukin-6. We examined whether CREB is involved in TNF--induced VSMC migration.
Methods and Results--TNF- induced CREB phosphorylation with a peak at 15 minutes of stimulation. Pharmacological inhibition of p38 mitogen-activated protein kinase (p38-MAPK) inhibited TNF--induced CREB phosphorylation. Adenovirus-mediated overexpression of dominant-negative form of CREB suppressed TNF--induced CREB phosphorylation and c-fos mRNA expression. VSMC migration was evaluated using a Boyden chamber. Overexpression of dominant-negative form of CREB suppressed VSMC migration as well as induction of Rac1 expression induced by TNF-. Overexpression of dominant-negative Rac1 also inhibited TNF--induced VSMC migration.
Conclusion--Our results suggest that p38-MAPK/CREB/Rac1 pathway plays a critical role in TNF--induced VSMC migration and may be a novel therapeutic target for vascular stenotic lesion.
Key words: migration • TNF-
•
CREB •
p38-MAPK •
Rac1
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