cAMP-response element-binding protein mediates tumor necrosis factor-α-induced vascular smooth muscle cell migration

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-α (TNF-α) 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-α-induced VSMC migration. Methods and Results-TNF-α induced CREB phosphorylation with a peak at 15 minutes of stimulation. Pharmacological inhibition of p38 mitogen-activated protein kinase (p38-MAPK) inhibited TNF-α-induced CREB phosphorylation. Adenovirus-mediated overexpression of dominant-negative form of CREB suppressed TNF-α-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-α. Overexpression of dominant-negative Rac1 also inhibited TNF-α-induced VSMC migration. Conclusion-Our results suggest that p38-MAPK/CREB/Rac1 pathway plays a critical role in TNF-α-induced VSMC migration and may be a novel therapeutic target for vascular stenotic lesion.