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 Kaplan, M. Articles by Aviram, M. Search for Related Content PubMed PubMed Citation Articles by Kaplan, M. Articles by Aviram, M. Related Collections Lipid and lipoprotein metabolism Mechanism of atherosclerosis/growth factors Genetically altered mice

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:386.)
© 2001 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Retention of Oxidized LDL by Extracellular Matrix Proteoglycans Leads to Its Uptake by Macrophages

An Alternative Approach to Study Lipoproteins Cellular Uptake

Marielle Kaplan; Michael Aviram

From the Lipid Research Laboratory, Bruce Rappaport Faculty of Medicine, Technion, The Rappaport Family Institute for Research in the Medical Sciences and Rambam Medical Center, Haifa, Israel.

Correspondence to Michael Aviram, DSc, Lipid Research Laboratory, Rambam Medical Center, Haifa 31096, Israel. E-mail aviram{at}tx.technion.ac.il

Abstract—Interaction between arterial macrophages and oxidized LDL (Ox-LDL) leads to foam cell formation, a critical step during early atherogenesis. Until now, cellular uptake of lipoproteins was studied through incubation of the media-soluble lipoprotein with cultured macrophages. However, as lipoproteins in the arterial wall are bound to subendothelial matrix, we questioned whether the retention (binding) of Ox-LDL to a macrophage-derived extracellular matrix (ECM) could lead to enhanced uptake by macrophages. The uptake of ECM-bound Ox-LDL by activated macrophages (by phorbol myristate acetate) was lipoprotein dose dependent, time dependent and higher (by 1.5-fold) than the uptake of ECM-bound native LDL. Preincubation of the ECM with lipoprotein lipase before the addition of Ox-LDL was essential for the uptake of ECM-bound Ox-LDL by the macrophages. After radiolabeling of the ECM glycosaminoglycans (GAGs), we found that ECM-bound Ox-LDL is taken up by the macrophages together with the ECM-GAG. Finally, these results were further confirmed through the use of ECM obtained from mouse peritoneal macrophages (MPMs), derived from atherosclerotic, apoE-deficient mice. In 24-week-old mice with developed atherosclerosis, the GAG content of their MPM-derived ECM increased by 52%, the ability of their MPM-derived ECM to bind Ox-LDL increased by 57%, and macrophage uptake of Ox-LDL that was retained by the MPM-derived ECM increased by 86%. In conclusion, the present study demonstrated that ECM-bound Ox-LDL is taken up by activated macrophages. This may represent a physiopathological phenomenon that leads to cholesterol and oxysterol accumulation in arterial macrophages, the hallmark of early atherosclerosis.

Key Words: extracellular matrix • binding • oxidized LDL • macrophages • atherosclerosis

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]

				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]

				G. Qiu, A. C. Ho, W. Yu, and J. S. Hill Suppression of endothelial or lipoprotein lipase in THP-1 macrophages attenuates proinflammatory cytokine secretion J. Lipid Res., February 1, 2007; 48(2): 385 - 394. [Abstract] [Full Text] [PDF]

				L. DeMaio, M. Rouhanizadeh, S. Reddy, A. Sevanian, J. Hwang, and T. K. Hsiai Oxidized phospholipids mediate occludin expression and phosphorylation in vascular endothelial cells Am J Physiol Heart Circ Physiol, February 1, 2006; 290(2): H674 - H683. [Abstract] [Full Text] [PDF]

				B. OSTERUD and E. BJORKLID Role of Monocytes in Atherogenesis Physiol Rev, October 1, 2003; 83(4): 1069 - 1112. [Abstract] [Full Text] [PDF]

				D. P. Germain, P. Boutouyrie, B. Laloux, and S. Laurent Arterial Remodeling and Stiffness in Patients With Pseudoxanthoma Elasticum Arterioscler. Thromb. Vasc. Biol., May 1, 2003; 23(5): 836 - 841. [Abstract] [Full Text] [PDF]

				T. B. Twickler, G. M. Dallinga-Thie, F. L. J. Visseren, W. R. de Vries, D. W. Erkelens, and H. P. F. Koppeschaar Induction of Postprandial Inflammatory Response in Adult Onset Growth Hormone Deficiency Is Related to Plasma Remnant-Like Particle-Cholesterol Concentration J. Clin. Endocrinol. Metab., March 1, 2003; 88(3): 1228 - 1233. [Abstract] [Full Text] [PDF]

				P. Boutouyrie, D. P. Germain, A.-I. Tropeano, B. Laloux, F. Carenzi, M. Zidi, X. Jeunemaitre, and S. Laurent Compressibility of the Carotid Artery in Patients With Pseudoxanthoma Elasticum Hypertension, November 1, 2001; 38(5): 1181 - 1184. [Abstract] [Full Text] [PDF]

				S. W. Sakr, R. J. Eddy, H. Barth, F. Wang, S. Greenberg, F. R. Maxfield, and I. Tabas The Uptake and Degradation of Matrix-bound Lipoproteins by Macrophages Require an Intact Actin Cytoskeleton, Rho Family GTPases, and Myosin ATPase Activity J. Biol. Chem., September 28, 2001; 276(40): 37649 - 37658. [Abstract] [Full Text] [PDF]