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(Hypertension. 2002;39:645.)
© 2002 American Heart Association, Inc.

Scientific Contributions

Native LDL Induces Proliferation of Human Vascular Smooth Muscle Cells via Redox-Mediated Activation of ERK 1/2 Mitogen-Activated Protein Kinases

Rudolf Locher; Ralf P. Brandes; Wilhelm Vetter; Matthias Barton

From the Departments of Internal Medicine, Medical Policlinic (W.V., M.B.), and Clinical Atherosclerosis Research Laboratory (R.L., M.B.), University Hospital, Zürich, Switzerland, and the Institut für Kardiovaskuläre Physiologie (R.P.B.), Klinikum der J. W. Goethe-Universität, Frankfurt/Main, Germany.

Correspondence to Matthias Barton, Department of Internal Medicine, Medical Policlinic, University Hospital, Rämistrasse 100, CH-8091 Zürich, Switzerland. E-mail bartonm{at}swissonline.ch

This study investigated mechanisms underlying native low-density lipoprotein (LDL)-stimulated proliferation of human vascular smooth muscle cells (VSMC). Experiments were performed to determine whether native LDL affects reactive oxygen species (ROS) formation and activity of extracellular signal-regulated kinase 1/2 (ERK1/2), and whether redox-sensitive pathways contribute to LDL-induced cell proliferation. Native LDL (100 µg/mL, 24 hours) increased cell proliferation (to 303 to 388% of control, P<0.0001) as determined by [methyl-³H] thymidine incorporation. This effect was completely blocked either by the antioxidants N-acetylcysteine, Tiron, or nordihydroguaiaretic acid; the flavin-inhibitor diphenylene iodonium; or superoxide dismutase (all P<0.0001), and partly blocked by ERK-inhibitor PD98059 or meclofenamate (P<0.01). Exposure of VSMC to native LDL for 20 minutes stimulated ROS formation, measured by dichlorodihydrofluorescein oxidation, and increased ERK1/2 activity by 3.1-fold (P<0.001). The latter effect was sensitive to MEK1/2 inhibitor PD98059 and Tiron (P<0.001), and in part to N-acetylcysteine or diphenylene iodonium (P<0.05). These results demonstrate that native LDL induces acute formation of ROS and subsequent activation of redox-sensitive ERK 1/2 mitogen-activated protein kinases, pathways that appear to be important for mitogenic signaling of native LDL in human vascular smooth muscle cells.

Key Words: antioxidants • atherosclerosis • kinase • lipoproteins • muscle, smooth, vascular

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