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 Klouche, M. Articles by Bhakdi, S. Search for Related Content PubMed PubMed Citation Articles by Klouche, M. Articles by Bhakdi, S. Related Collections Smooth muscle proliferation and differentiation

(Circulation. 2000;101:1799.)
© 2000 American Heart Association, Inc.

Clinical Investigation and Reports

Enzymatically Degraded, Nonoxidized LDL Induces Human Vascular Smooth Muscle Cell Activation, Foam Cell Transformation, and Proliferation

Mariam Klouche, MD; Stefan Rose-John, PhD; Walther Schmiedt, MD; Sucharit Bhakdi, MD

From the Institute of Medical Microbiology (M.K., S.B.), Department of Internal Medicine (S.R.-J.), Section of Pathophysiology and Department of Heart and Thoracic Surgery (W.S.), University of Mainz, Germany.

Correspondence to Dr Mariam Klouche, Institute of Medical Microbiology, University of Mainz, Hochhaus am Augustusplatz, 55101 Mainz, Germany. E-mail: klouche{at}mail.uni-mainz.de

Background—Enzymatic, nonoxidative modification transforms LDL to an atherogenic molecule (E-LDL) that activates complement and macrophages and is present in early atherosclerotic lesions.

Methods and Results—We report on the atherogenic effects of E-LDL on human vascular smooth muscle cells (SMC). E-LDL accumulated in these cells, and this was accompanied by selective induction of monocyte chemotactic protein-1 in the absence of effects on the expression of interleukin (IL)-8, RANTES, or monocyte inflammatory proteins-1 and -ß). Furthermore, E-LDL stimulated the expression of gp130, the signal-transducing chain of the IL-6 receptor (IL-6R) family, and the secretion of IL-6. E-LDL invoked mitogenic effects on SMC through 2 mechanisms. First, an autocrine mitogenic circuit involving platelet-derived growth factor and fibroblast growth factor-ß was induced. Second, upregulation of gp130 rendered SMC sensitive to transsignaling through the IL-6/sIL-6R activation pathway. Because E-LDL promoted release of both IL-6 and sIL-6R from macrophages, application of macrophage cell supernatants to prestimulated SMC provoked a pronounced and sustained proliferation of the cells.

Conclusions—E-LDL can invoke alterations in SMC that are characteristic of the evolving atherosclerotic lesion.

Key Words: atherosclerosis • lipoproteins • cells • muscle, smooth • enzymes

This article has been cited by other articles:

				A. C. Doran, N. Meller, and C. A. McNamara Role of Smooth Muscle Cells in the Initiation and Early Progression of Atherosclerosis Arterioscler Thromb Vasc Biol, May 1, 2008; 28(5): 812 - 819. [Abstract] [Full Text] [PDF]

				H. Loppnow, K. Werdan, and M. Buerke Invited review: Vascular cells contribute to atherosclerosis by cytokine- and innate-immunity-related inflammatory mechanisms Innate Immunity, April 1, 2008; 14(2): 63 - 87. [Abstract] [PDF]

				H.R.S. Girn, N.M. Orsi, and S. Homer-Vanniasinkam An overview of cytokine interactions in atherosclerosis and implications for peripheral arterial disease Vascular Medicine, November 1, 2007; 12(4): 299 - 309. [Abstract] [PDF]

				S. Demyanets, C. Kaun, K. Rychli, G. Rega, S. Pfaffenberger, T. Afonyushkin, V. N. Bochkov, G. Maurer, K. Huber, and J. Wojta The inflammatory cytokine oncostatin M induces PAI-1 in human vascular smooth muscle cells in vitro via PI 3-kinase and ERK1/2-dependent pathways Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1962 - H1968. [Abstract] [Full Text] [PDF]

				G. O. Angheloiu, J. T. Arendt, M. G. Muller, A. S. Haka, I. Georgakoudi, J. T. Motz, O. R. Scepanovic, B. D. Kuban, J. Myles, F. Miller, et al. Intrinsic Fluorescence and Diffuse Reflectance Spectroscopy Identify Superficial Foam Cells in Coronary Plaques Prone to Erosion Arterioscler Thromb Vasc Biol, July 1, 2006; 26(7): 1594 - 1600. [Abstract] [Full Text] [PDF]

				I. Dobreva, G. Waeber, R. W. James, and C. Widmann Interleukin-8 Secretion by Fibroblasts Induced by Low Density Lipoproteins Is p38 MAPK-dependent and Leads to Cell Spreading and Wound Closure J. Biol. Chem., January 6, 2006; 281(1): 199 - 205. [Abstract] [Full Text] [PDF]

				S. A. Jones Directing Transition from Innate to Acquired Immunity: Defining a Role for IL-6 J. Immunol., September 15, 2005; 175(6): 3463 - 3468. [Abstract] [Full Text] [PDF]

				J. X. Rong, J. Kusunoki, P. Oelkers, S. L. Sturley, and E. A. Fisher Acyl-CoenzymeA (CoA):Cholesterol Acyltransferase Inhibition in Rat and Human Aortic Smooth Muscle Cells Is Nontoxic and Retards Foam Cell Formation Arterioscler Thromb Vasc Biol, January 1, 2005; 25(1): 122 - 127. [Abstract] [Full Text] [PDF]

				M. Torzewski, P. Suriyaphol, K. Paprotka, L. Spath, V. Ochsenhirt, A. Schmitt, S.-R. Han, M. Husmann, V. B. Gerl, S. Bhakdi, et al. Enzymatic Modification of Low-Density Lipoprotein in the Arterial Wall: A New Role for Plasmin and Matrix Metalloproteinases in Atherogenesis Arterioscler Thromb Vasc Biol, November 1, 2004; 24(11): 2130 - 2136. [Abstract] [Full Text] [PDF]

				S. W. Lindemann, C. C. Yost, M. M. Denis, T. M. McIntyre, A. S. Weyrich, and G. A. Zimmerman Neutrophils alter the inflammatory milieu by signal-dependent translation of constitutive messenger RNAs PNAS, May 4, 2004; 101(18): 7076 - 7081. [Abstract] [Full Text] [PDF]

				J. X. Rong, M. Shapiro, E. Trogan, and E. A. Fisher Transdifferentiation of mouse aortic smooth muscle cells to a macrophage-like state after cholesterol loading PNAS, November 11, 2003; 100(23): 13531 - 13536. [Abstract] [Full Text] [PDF]

				M. A. Nowell, P. J. Richards, S. Horiuchi, N. Yamamoto, S. Rose-John, N. Topley, A. S. Williams, and S. A. Jones Soluble IL-6 Receptor Governs IL-6 Activity in Experimental Arthritis: Blockade of Arthritis Severity by Soluble Glycoprotein 130 J. Immunol., September 15, 2003; 171(6): 3202 - 3209. [Abstract] [Full Text] [PDF]

				N. Auge, O. Rebai, J. Lepetit-Thevenin, N. Bruneau, J.-C. Thiers, E. Mas, D. Lombardo, A. Negre-Salvayre, and A. Verine Pancreatic Bile Salt-Dependent Lipase Induces Smooth Muscle Cells Proliferation Circulation, July 8, 2003; 108(1): 86 - 91. [Abstract] [Full Text] [PDF]

				J. H. Von der Thusen, J. Kuiper, T. J. C. Van Berkel, and E. A. L. Biessen Interleukins in Atherosclerosis: Molecular Pathways and Therapeutic Potential Pharmacol. Rev., March 1, 2003; 55(1): 133 - 166. [Abstract] [Full Text] [PDF]

				P. Suriyaphol, D. Fenske, U. Zahringer, S.-R. Han, S. Bhakdi, and M. Husmann Enzymatically Modified Nonoxidized Low-Density Lipoprotein Induces Interleukin-8 in Human Endothelial Cells: Role of Free Fatty Acids Circulation, November 12, 2002; 106(20): 2581 - 2587. [Abstract] [Full Text] [PDF]

				C. Kluft, R. Kleemann, and M.P.M. de Maat How best to counteract the enemies? By controlling inflammation in the coronary circulation Eur. Heart J. Suppl., November 1, 2002; 4(suppl_G): G53 - G65. [Abstract] [PDF]

				I. GOUNI-BERTHOLD and A. SACHINIDIS Does the coronary risk factor low density lipoprotein alter growth and signaling in vascular smooth muscle cells? FASEB J, October 1, 2002; 16(12): 1477 - 1487. [Abstract] [Full Text] [PDF]

				B. S. Sachais, A. Kuo, T. Nassar, J. Morgan, K. Kariko, K. J. Williams, M. Feldman, M. Aviram, N. Shah, L. Jarett, et al. Platelet factor 4 binds to low-density lipoprotein receptors and disrupts the endocytic itinerary, resulting in retention of low-density lipoprotein on the cell surface Blood, May 15, 2002; 99(10): 3613 - 3622. [Abstract] [Full Text] [PDF]

				D. Kielar, W. Dietmaier, T. Langmann, C. Aslanidis, M. Probst, M. Naruszewicz, and G. Schmitz Rapid Quantification of Human ABCA1 mRNA in Various Cell Types and Tissues by Real-Time Reverse Transcription-PCR Clin. Chem., December 1, 2001; 47(12): 2089 - 2097. [Abstract] [Full Text] [PDF]