cAMP response element-binding protein mediates thrombin-induced proliferation of vascular smooth muscle cells

Thrombin is a potent mitogen for vascular smooth muscle cells (VSMCs) and p lays an important role in the progression of atherosclerosis. Although rece nt reports have suggested that cAMP response element-binding protein (CREB) is necessary for the survival of neuronal cells, the role of CREB in VSMC proliferation is not determined. We examined the role of CREB in thrombin-i nduced VSMC proliferation and the effect of thrombin on phosphorylation of CREB at Ser133, which is a critical marker for activation by Western blot a nalysis. Thrombin induced phosphorylation of CREB in a dose-dependent manne r. An oligopeptide, SFLLRN, which activates the thrombin receptor, also ind uced the phosphorylation of CREB. Inhibition of extracellular signal-regula ted protein kinase or inhibition of p38 mitogen-activated protein kinase su ppressed the thrombin-induced CREB phosphorylation. Inhibition of the epide rmal growth factor receptor by AG1478 also inhibited the thrombin-induced C REB phosphorylation. Overexpression of the dominant-negative form of CREB i nhibited thrombin-induced a fos mRNA expression and incorporation of [H-3]t hymidine and [H-3]leucine. These results suggest that CREB-dependent gene t ranscription plays a critical role in. thrombin-induced proliferation and h ypertrophy of VSMCs. Transactivation of the epidermal growth factor recepto r and 2 mitogen-activated protein kinase pathways are involved in this proc ess. CREB may be a novel transcription factor mediating the vascular remode ling process induced by thrombin.