Atherogenic Properties of Enzymatically Degraded LDL

Selective Induction of MCP-1 and Cytotoxic Effects on Human Macrophages

From the Institute of Medical Microbiology and Hygiene, Johannes-Gutenberg University of Mainz, Mainz, Germany.

Correspondence to Dr Mariam Klouche, Johannes-Gutenberg University of Mainz, Institute of Medical Microbiology, Obere Zahlbacher Strasse, 55101 Mainz, Germany. E-mail klouche{at}mail.Uni-Mainz.de

Abstract—The mechanisms underlying the selective accumulation of macrophages in early atherosclerotic lesions are poorly understood but are likely to be related to specific properties of altered low density lipoprotein (LDL) deposited in the subendothelium. Enzymatic, nonoxidative degradation of LDL converts the lipoprotein to a potentially atherogenic moiety, enzymatically altered LDL (E-LDL), which activates complement and is rapidly taken up by human macrophages via a scavenger receptor–dependent pathway. Immunohistological evidence indicates that E-LDL is present in an extracellular location in the early lesion. We report that E-LDL causes massive release of monocyte chemotactic protein 1 (MCP-1) from macrophages and that expression of interleukin 8 or RANTES remains unchanged. Release of MCP-1 was preceded by a rapid expression of MCP-1 mRNA, which was detectable after 15 minutes, reached maximum levels after 1 hour, and remained detectable for 12 hours after exposure to concentrations as low as 10 µg/mL E-LDL. MCP-1 mRNA induction and protein release by E-LDL exceeded that evoked by oxidized LDL. Release of MCP-1 was dependent on de novo protein synthesis and on the activity of tyrosine kinases. At higher concentrations, E-LDL, but not oxidized LDL, exerted toxic effects on macrophages that in part appeared to be due to apoptosis. The results show that E-LDL possesses major properties of an atherogenic lipoprotein.

Key Words: atherosclerosis • macrophages • LDL • monocyte chemotactic protein 1 • toxicity

This article has been cited by other articles:

				Y. Nakashima, T. N. Wight, and K. Sueishi Early atherosclerosis in humans: role of diffuse intimal thickening and extracellular matrix proteoglycans Cardiovasc Res, July 1, 2008; 79(1): 14 - 23. [Abstract] [Full Text] [PDF]

				S. K. Singh, M. V. Suresh, D. C. Prayther, J. P. Moorman, A. E. Rusinol, and A. Agrawal C-Reactive Protein-Bound Enzymatically Modified Low-Density Lipoprotein Does Not Transform Macrophages into Foam Cells J. Immunol., March 15, 2008; 180(6): 4316 - 4322. [Abstract] [Full Text] [PDF]

				J. K. Hakala, K. A. Lindstedt, P. T. Kovanen, and M. O. Pentikainen Low-Density Lipoprotein Modified by Macrophage-Derived Lysosomal Hydrolases Induces Expression and Secretion of IL-8 Via p38 MAPK and NF-{kappa}B by Human Monocyte-Derived Macrophages Arterioscler. Thromb. Vasc. Biol., November 1, 2006; 26(11): 2504 - 2509. [Abstract] [Full Text] [PDF]

				E. Paffen and M. P.M. deMaat C-reactive protein in atherosclerosis: A causal factor? Cardiovasc Res, July 1, 2006; 71(1): 30 - 39. [Abstract] [Full Text] [PDF]

				K. Reifenberg, H.-A. Lehr, D. Baskal, E. Wiese, S. C. Schaefer, S. Black, D. Samols, M. Torzewski, K. J. Lackner, M. Husmann, et al. Role of C-Reactive Protein in Atherogenesis: Can the Apolipoprotein E Knockout Mouse Provide the Answer? Arterioscler. Thromb. Vasc. Biol., August 1, 2005; 25(8): 1641 - 1646. [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. Bhakdi, M. Torzewski, K. Paprotka, S. Schmitt, H. Barsoom, P. Suriyaphol, S.-R. Han, K. J. Lackner, and M. Husmann Possible Protective Role for C-Reactive Protein in Atherogenesis: Complement Activation by Modified Lipoproteins Halts Before Detrimental Terminal Sequence Circulation, April 20, 2004; 109(15): 1870 - 1876. [Abstract] [Full Text] [PDF]

				V. Matthews, B. Schuster, S. Schutze, I. Bussmeyer, A. Ludwig, C. Hundhausen, T. Sadowski, P. Saftig, D. Hartmann, K.-J. Kallen, et al. Cellular Cholesterol Depletion Triggers Shedding of the Human Interleukin-6 Receptor by ADAM10 and ADAM17 (TACE) J. Biol. Chem., October 3, 2003; 278(40): 38829 - 38839. [Abstract] [Full Text] [PDF]

				S.-R. Han, A. Momeni, K. Strach, P. Suriyaphol, D. Fenske, K. Paprotka, S. I. Hashimoto, M. Torzewski, S. Bhakdi, and M. Husmann Enzymatically Modified LDL Induces Cathepsin H in Human Monocytes: Potential Relevance in Early Atherogenesis Arterioscler. Thromb. Vasc. Biol., April 1, 2003; 23(4): 661 - 667. [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]

				M. Namiki, S. Kawashima, T. Yamashita, M. Ozaki, T. Hirase, T. Ishida, N. Inoue, K.-i. Hirata, A. Matsukawa, R. Morishita, et al. Local Overexpression of Monocyte Chemoattractant Protein-1 at Vessel Wall Induces Infiltration of Macrophages and Formation of Atherosclerotic Lesion: Synergism With Hypercholesterolemia Arterioscler. Thromb. Vasc. Biol., January 1, 2002; 22(1): 115 - 120. [Abstract] [Full Text] [PDF]

				H.-S. Liao, T. Kodama, and Y.-J. Geng Expression of Class A Scavenger Receptor Inhibits Apoptosis of Macrophages Triggered by Oxidized Low Density Lipoprotein and Oxysterol Arterioscler. Thromb. Vasc. Biol., August 1, 2000; 20(8): 1968 - 1975. [Abstract] [Full Text] [PDF]

				M. W. Anthonsen, D. Stengel, D. Hourton, E. Ninio, and B. Johansen Mildly Oxidized LDL Induces Expression of Group IIa Secretory Phospholipase A2 in Human Monocyte-Derived Macrophages Arterioscler. Thromb. Vasc. Biol., May 1, 2000; 20(5): 1276 - 1282. [Abstract] [Full Text] [PDF]

				M. Klouche, S. Rose-John, W. Schmiedt, and S. Bhakdi Enzymatically Degraded, Nonoxidized LDL Induces Human Vascular Smooth Muscle Cell Activation, Foam Cell Transformation, and Proliferation Circulation, April 18, 2000; 101(15): 1799 - 1805. [Abstract] [Full Text] [PDF]

				S. Parthasarathy, N. Santanam, S. Ramachandran, and O. Meilhac Oxidants and antioxidants in atherogenesis: an appraisal J. Lipid Res., December 1, 1999; 40(12): 2143 - 2157. [Abstract] [Full Text] [PDF]

				M. Klouche, S. Bhakdi, M. Hemmes, and S. Rose-John Novel Path to Activation of Vascular Smooth Muscle Cells: Up-Regulation of gp130 Creates an Autocrine Activation Loop by IL-6 and Its Soluble Receptor J. Immunol., October 15, 1999; 163(8): 4583 - 4589. [Abstract] [Full Text] [PDF]

				S. Bhakdi, M. Torzewski, M. Klouche, and M. Hemmes Complement and Atherogenesis : Binding of CRP to Degraded, Nonoxidized LDL Enhances Complement Activation Arterioscler. Thromb. Vasc. Biol., October 1, 1999; 19(10): 2348 - 2354. [Abstract] [Full Text] [PDF]

				M. Klouche, A. E. May, M. Hemmes, M. Meßner, S. M. Kanse, K. T. Preissner, and S. Bhakdi Enzymatically Modified, Nonoxidized LDL Induces Selective Adhesion and Transmigration of Monocytes and T-Lymphocytes Through Human Endothelial Cell Monolayers Arterioscler. Thromb. Vasc. Biol., March 1, 1999; 19(3): 784 - 793. [Abstract] [Full Text] [PDF]

				P. Avirutnan, P. Malasit, B. Seliger, S. Bhakdi, and M. Husmann Dengue Virus Infection of Human Endothelial Cells Leads to Chemokine Production, Complement Activation, and Apoptosis J. Immunol., December 1, 1998; 161(11): 6338 - 6346. [Abstract] [Full Text] [PDF]

				W. Schmiedt, R. Kinscherf, H.-P. Deigner, H. Kamencic, O. Nauen, J. Kilo, H. Oelert, J. Metz, and S. Bhakdi Complement C6 Deficiency Protects Against Diet-Induced Atherosclerosis in Rabbits Arterioscler. Thromb. Vasc. Biol., November 1, 1998; 18(11): 1790 - 1795. [Abstract] [Full Text] [PDF]