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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:1794.)
© 2003 American Heart Association, Inc.

Vascular Biology

Withdrawal of Cerivastatin Induces Monocyte Chemoattractant Protein 1 and Tissue Factor Expression in Cultured Vascular Smooth Muscle Cells

R.P. Brandes; S. Beer; T. Ha; R. Busse

From the Institut für Kardiovaskuläre Physiologie, Klinikum der J.W. Goethe-Universität, Frankfurt am Main, Germany.

Correspondence to Ralf P. Brandes, MD, Institut für Kardiovaskuläre Physiologie, Klinikum der J.W. Goethe-Universität, Theodor-Stern-Kai 7, D-60596 Frankfurt am Main, Germany. E-mail r.brandes{at}em.uni-frankfurt.de

Objective— The withdrawal of 3-hydroxy-3-methylglutaryl-coenzyme A-reductase inhibitors (statins) deteriorates endothelial function. We determined in vascular smooth muscle cells whether statin withdrawal leads to the expression of proinflammatory genes involved in the development and progression of arteriosclerosis.

Methods and Results— The withdrawal of cerivastatin from pretreated vascular smooth muscle cells induced an increase in monocyte chemoattractant protein 1 (MCP-1) and tissue factor (TF) mRNA expression and enhanced MCP-1 secretion as well as cell surface TF activity. In the presence of cerivastatin, this effect was mimicked by geranylgeranyl pyrophosphate or mevalonate. Withdrawal-induced MCP-1 expression was sensitive to PD98059, SB203580, and diphenylene iodonium, suggesting an involvement of extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, and the NADPH oxidase. Withdrawal increased the activity of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase and enhanced radical generation. Because the latter effect may result from an Rac-mediated activation of the NADPH oxidase, the effect of withdrawal on Rac translocation was studied. Statin treatment induced an increase in Rac-1 content in the cytoplasm. On withdrawal, however, an "overshoot" translocation of Rac to the plasma membrane occurred.

Conclusions— These observations suggest that statin withdrawal results in the activation of Rac and enhanced oxidative stress. The subsequent activation of redox-activated signal-transduction cascades results in the expression of MCP-1 and TF.

Key Words: statins • 3-hydroxy-3-methylglutaryl-coenzyme A-reductase inhibitors • tissue factor • arteriosclerosis • mitogen-activated protein kinase

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