This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Locher, R. Articles by Barton, M. Search for Related Content PubMed PubMed Citation Articles by Locher, R. Articles by Barton, M. Related Collections Pathophysiology Risk Factors Cell signalling/signal transduction Smooth muscle proliferation and differentiation Lipid and lipoprotein metabolism Oxidant stress Mechanism of atherosclerosis/growth factors Other Vascular biology

(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

This article has been cited by other articles:

				T. Padro, E. Pena, M. Garcia-Arguinzonis, V. Llorente-Cortes, and L. Badimon Low-density lipoproteins impair migration of human coronary vascular smooth muscle cells and induce changes in the proteomic profile of myosin light chain Cardiovasc Res, January 1, 2008; 77(1): 211 - 220. [Abstract] [Full Text] [PDF]

				M. Barton, R. Minotti, and E. Haas Inflammation and Atherosclerosis Circ. Res., October 12, 2007; 101(8): 750 - 751. [Full Text] [PDF]

				L. Ding, A. Chapman, R. Boyd, and H. D. Wang ERK activation contributes to regulation of spontaneous contractile tone via superoxide anion in isolated rat aorta of angiotensin II-induced hypertension Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H2997 - H3005. [Abstract] [Full Text] [PDF]

				E. Haas, M. R. Meyer, U. Schurr, I. Bhattacharya, R. Minotti, H. H. Nguyen, A. Heigl, M. Lachat, M. Genoni, and M. Barton Differential Effects of 17{beta}-Estradiol on Function and Expression of Estrogen Receptor {alpha}, Estrogen Receptor {beta}, and GPR30 in Arteries and Veins of Patients With Atherosclerosis Hypertension, June 1, 2007; 49(6): 1358 - 1363. [Abstract] [Full Text] [PDF]

				T. Traupe, C. D. Stettler, H. Li, E. Haas, I. Bhattacharya, R. Minotti, and M. Barton Distinct Roles of Estrogen Receptors {alpha} and {beta} Mediating Acute Vasodilation of Epicardial Coronary Arteries Hypertension, June 1, 2007; 49(6): 1364 - 1370. [Abstract] [Full Text] [PDF]

				H. ten Freyhaus, M. Huntgeburth, K. Wingler, J. Schnitker, A. T. Baumer, M. Vantler, M. M. Bekhite, M. Wartenberg, H. Sauer, and S. Rosenkranz Novel Nox inhibitor VAS2870 attenuates PDGF-dependent smooth muscle cell chemotaxis, but not proliferation Cardiovasc Res, July 15, 2006; 71(2): 331 - 341. [Abstract] [Full Text] [PDF]

				G. Muller, R. A. Catar, B. Niemann, M. Barton, L. Knels, M. Wendel, and H. Morawietz Upregulation of endothelin receptor B in human endothelial cells by low-density lipoproteins. Experimental Biology and Medicine, June 1, 2006; 231(6): 766 - 771. [Abstract] [Full Text] [PDF]

				A. R. Chade, O. P. Mushin, X. Zhu, M. Rodriguez-Porcel, J. P. Grande, S. C. Textor, A. Lerman, and L. O. Lerman Pathways of Renal Fibrosis and Modulation of Matrix Turnover in Experimental Hypercholesterolemia Hypertension, October 1, 2005; 46(4): 772 - 779. [Abstract] [Full Text] [PDF]

				J. Martinez-Gonzalez and L. Badimon The NR4A subfamily of nuclear receptors: new early genes regulated by growth factors in vascular cells Cardiovasc Res, February 15, 2005; 65(3): 609 - 618. [Abstract] [Full Text] [PDF]

				J. Rius, J. Martinez-Gonzalez, J. Crespo, and L. Badimon Involvement of Neuron-Derived Orphan Receptor-1 (NOR-1) in LDL-Induced Mitogenic Stimulus in Vascular Smooth Muscle Cells: Role of CREB Arterioscler. Thromb. Vasc. Biol., April 1, 2004; 24(4): 697 - 702. [Abstract] [Full Text] [PDF]

				S.-W. Ryoo, D.-U. Kim, M. Won, K.-S. Chung, Y.-J. Jang, G.-T. Oh, S.-K. Park, P.-J. Maeng, H.-S. Yoo, and K.-L. Hoe Native LDL induces interleukin-8 expression via H2O2, p38 Kinase, and activator protein-1 in human aortic smooth muscle cells Cardiovasc Res, April 1, 2004; 62(1): 185 - 193. [Abstract] [Full Text] [PDF]

				T. Bleeke, H. Zhang, N. Madamanchi, C. Patterson, and J. E. Faber Catecholamine-Induced Vascular Wall Growth Is Dependent on Generation of Reactive Oxygen Species Circ. Res., January 9, 2004; 94(1): 37 - 45. [Abstract] [Full Text] [PDF]

				H. C. Atherton, G. Jones, and H. Danahay IL-13-induced changes in the goblet cell density of human bronchial epithelial cell cultures: MAP kinase and phosphatidylinositol 3-kinase regulation Am J Physiol Lung Cell Mol Physiol, September 1, 2003; 285(3): L730 - L739. [Abstract] [Full Text] [PDF]

				J. Xu, B. Jian, R. Chu, Z. Lu, Q. Li, J. Dunlop, S. Rosenzweig-Lipson, P. McGonigle, R. J. Levy, and B. Liang Serotonin Mechanisms in Heart Valve Disease II: The 5-HT2 Receptor and Its Signaling Pathway in Aortic Valve Interstitial Cells Am. J. Pathol., December 1, 2002; 161(6): 2209 - 2218. [Abstract] [Full Text] [PDF]