cAMP-response element-binding protein mediates tumor necrosis factor-alpha-induced vascular smooth muscle cell migration.
Arteriosclerosis, thrombosis, and vascular biology 2004 Sep 1; 24(9):1634-9
Ono H H, Ichiki T T, Fukuyama K K, Iino N N, Masuda S S, Egashira K K, Takeshita A A
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, 812-8582 Fukuoka, Japan.
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-alpha (TNF-alpha) 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-alpha-induced VSMC migration. METHODS AND RESULTS: TNF-alpha induced CREB phosphorylation with a peak at 15 minutes of stimulation. Pharmacological inhibition of p38 mitogen-activated protein kinase (p38-MAPK) inhibited TNF-alpha-induced CREB phosphorylation. Adenovirus-mediated overexpression of dominant-negative form of CREB suppressed TNF-alpha-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-alpha. Overexpression of dominant-negative Rac1 also inhibited TNF-alpha-induced VSMC migration. CONCLUSIONS: Our results suggest that p38-MAPK/CREB/Rac1 pathway plays a critical role in TNF-alpha-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-alpha, a potent migration factor for VSMCs, activated CREB through p38 mitogen-activated protein kinase (p38-MAPK). CREB inhibition suppressed TNF-alpha-induced VSMC migration and Rac1 expression. These results suggest p38-MAPK/CREB/Rac1 pathway mediates TNF-alpha-induced VSMC migration.