This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 24/9/1634    most recent 01.ATV.0000138052.86051.0dv1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ono, H. Articles by Takeshita, A. Search for Related Content PubMed PubMed Citation Articles by Ono, H. Articles by Takeshita, A. Related Collections Gene regulation Growth factors/cytokines Smooth muscle proliferation and differentiation

(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

This article has been cited by other articles:

				K. R. Chava, M. Karpurapu, D. Wang, M. Bhanoori, V. Kundumani-Sridharan, Q. Zhang, T. Ichiki, W. C. Glasgow, and G. N. Rao CREB-Mediated IL-6 Expression Is Required for 15(S)-Hydroxyeicosatetraenoic Acid-Induced Vascular Smooth Muscle Cell Migration Arterioscler Thromb Vasc Biol, June 1, 2009; 29(6): 809 - 815. [Abstract] [Full Text] [PDF]

				K. Venkatachalam, B. Venkatesan, A. J. Valente, P. C. Melby, S. Nandish, J. E. B. Reusch, R. A. Clark, and B. Chandrasekar WISP1, a Pro-mitogenic, Pro-survival Factor, Mediates Tumor Necrosis Factor-{alpha} (TNF-{alpha})-stimulated Cardiac Fibroblast Proliferation but Inhibits TNF-{alpha}-induced Cardiomyocyte Death J. Biol. Chem., May 22, 2009; 284(21): 14414 - 14427. [Abstract] [Full Text] [PDF]

				S. Jalvy, M.-A. Renault, L. L. S. Leen, I. Belloc, J. Bonnet, A.-P. Gadeau, and C. Desgranges Autocrine expression of osteopontin contributes to PDGF-mediated arterial smooth muscle cell migration Cardiovasc Res, September 1, 2007; 75(4): 738 - 747. [Abstract] [Full Text] [PDF]

				H. Ohtsubo, T. Ichiki, R. Miyazaki, K. Inanaga, I. Imayama, Y. Hashiguchi, J. Sadoshima, and K. Sunagawa Inducible cAMP Early Repressor Inhibits Growth of Vascular Smooth Muscle Cell Arterioscler Thromb Vasc Biol, July 1, 2007; 27(7): 1549 - 1555. [Abstract] [Full Text] [PDF]

				S. Jalvy, M.-A. Renault, L. Lam Shang Leen, I. Belloc, A. Reynaud, A.-P. Gadeau, and C. Desgranges CREB Mediates UTP-Directed Arterial Smooth Muscle Cell Migration and Expression of the Chemotactic Protein Osteopontin via Its Interaction with Activator Protein-1 Sites Circ. Res., May 11, 2007; 100(9): 1292 - 1299. [Abstract] [Full Text] [PDF]

				C. V. Garat, D. Fankell, P. F. Erickson, J. E.-B. Reusch, N. N. Bauer, I. F. McMurtry, and D. J. Klemm Platelet-Derived Growth Factor BB Induces Nuclear Export and Proteasomal Degradation of CREB via Phosphatidylinositol 3-Kinase/Akt Signaling in Pulmonary Artery Smooth Muscle Cells. Mol. Cell. Biol., July 1, 2006; 26(13): 4934 - 4948. [Abstract] [Full Text] [PDF]

				N. Dronadula, F. Rizvi, E. Blaskova, Q. Li, and G. N. Rao Involvement of cAMP-response element binding protein-1 in arachidonic acid-induced vascular smooth muscle cell motility J. Lipid Res., April 1, 2006; 47(4): 767 - 777. [Abstract] [Full Text] [PDF]

				T. Ichiki Role of cAMP Response Element Binding Protein in Cardiovascular Remodeling: Good, Bad, or Both? Arterioscler Thromb Vasc Biol, March 1, 2006; 26(3): 449 - 455. [Abstract] [Full Text] [PDF]