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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:1634.)
© 2004 American Heart Association, Inc.

Vascular Biology

cAMP-Response Element-Binding Protein Mediates Tumor Necrosis Factor-–Induced Vascular Smooth Muscle Cell Migration

Hiroki Ono; Toshihiro Ichiki; Kae Fukuyama; Naoko Iino; Satoko Masuda; Kensuke Egashira; Akira Takeshita

From the Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.

Correspondence to Toshihiro Ichiki, MD, Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, 812-8582 Fukuoka, Japan. 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 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.

Migration of vascular smooth muscle cells (VSMCs) contributes to formation of vascular stenotic lesions. TNF-, a potent migration factor for VSMCs, activated CREB through p38 mitogen-activated protein kinase (p38-MAPK). CREB inhibition suppressed TNF-–induced VSMC migration and Rac1 expression. These results suggest p38-MAPK/CREB/Rac1 pathway mediates TNF-–induced VSMC migration.

Key Words: migration • TNF- • CREB • p38-MAPK • Rac1

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