Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 24, Issue 9, Pages 1634-1639Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.ATV.0000138052.86051.0d
Keywords
migration; TNF-alpha; CREB; p38-MAPK; Rac1
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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. Conclusion - 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.
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