Potential roles of tyrosine phosphatase mkp-1 in the proliferation of rat vascular smooth muscle cells

The proliferation and migration of arterial smooth muscle cells plays an important role in the pathological process of arteriosclerosis. A number of cytokines and growth factors are upregulated and bind to their respective receptors, which in turn activate multiple signal transduction pathways leading ultimately to the activation of MAP kinases. These kinases in turn relay signals to the nucleus that result in activation of the previously quiescent smooth muscle cell. The activity of MAP kinases is countered by phosphatases. In this report we investigate the potential role of a dual tyrosine phosphatase, MAP kinase phosphatase 1 (MKP-1), in the proliferation of smooth muscle cells. We show that MKP-1 is highly expressed in vascular tissues. In situ hybridization demonstrated that the expression of MKP-1 message was mainly localized in the arterial smooth muscle layer. Following balloon injury of the carotid artery in the rat, the expression of MKP-1 was greatly reduced, while MAP kinases, especially p44 MAP kinase, were activated. The time course of reduction of the MKP-1 message correlated with an increase in tyrosine phosphorylation and an elevation of the enzymatic activity of p44 MAP kinase. A vascular smooth muscle cell line permanently overexpressing MKP-1 showed inhibition of cell growth with growth arrest in the G1 phase and blockade of entry into the S phase. These findings demonstrate that reduction of MKP-1 expression may contribute in part to the proliferation of smooth muscle cells after vascular damage, probably through a decrease in the dephosphorylation of activated MAP kinases, especially p44 MAP kinase.