COMMENTARIES

Carbamylated LDL Induces Monocyte Adhesion to Endothelial Cells

Alexei G. Basnakian, M.D., Ph.D., Division of Nephrology,
Department of Internal Medicine,
University of Arkansas for Medical Sciences,
Little Rock, AR 72205,
USA

Our recent study [1] was undertaken to determine whether monocyte adhesion to endothelial cells can be induced by carbamylated LDL (cLDL) and to identify the adhesion molecules involved in this process. We utilized U937 monocyte cells and human coronary artery endothelial cells (HCAEC), commonly used for studies of monocyte adhesion. We demonstrated that cLDL induces intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) on endothelial cells, and the role of these adhesion molecules in the attraction of monocytes in vitro. Inactivation of ICAM-1 and VCAM-1 by RNA interference (RNAi) or inhibiting antibody strongly protected against the adhesion of monocytes to endothelial cells, thus providing evidence for the potential importance of these mechanisms in cLDL-mediated atherosclerosis. Carbamylated LDL had no effect on MCP-1 or P-selectin. As opposed to cLDL, oxLDL, the most studied modified LDL, was previously shown to induce the expression of P-selectin [2] and MCP-1 [3,4].

          Carbamylated LDL is a recently identified type of modified LDL that seems to be important in atherosclerosis in humans [5-8]. It is generated by irreversible chemical modification of the protein component of the LDL particle, apolipoprotein B (ApoB) by urea-derived cyanate present in human blood plasma [5]. Plasma levels of cLDL as determined by sandwich ELISA methods vary in a higher range of concentrations than oxidized LDL (oxLDL), which makes it the most abundant LDL isoform of human plasma [7]. The elevation of blood urea in uremic patients causes a proportional increase of plasma cLDL [7]. The LDL of chronic renal failure patients on dialysis was shown to induce greater monocyte-endothelial cell adhesion [9]. A higher level of plasma cLDL correlates with atherosclerosis in uremic patients [10]. Our recent study showed that cLDL induced a variety of damaging stimuli to endothelial and vascular smooth muscle cells, all of which are attributed to atherosclerosis [6]. These include incorporation by endothelial cells, cytotoxicity towards endothelial cells, and the induction of vascular smooth muscle cell proliferation.

          Monocyte (leukocyte) adhesion to activated vascular endothelial cells and their migration into the vessel wall is the critical event in the initiation of atherosclerosis. This process is caused by the upregulation of adhesion molecules on endothelial cells and an increased expression in the vascular wall of chemotactic factors to monocytes. Highly specific adhesive interactions between monocytes and endothelial cells are mediated by three main families of receptors: members of the immunoglobulin superfamily, selectins, and integrins. Recent studies indicate that ICAM-1 and VCAM-1, members of the immunoglobulin superfamily, are the most common participants in monocyte attraction induced by different stimuli [11-15]. The expression of adhesion molecules and monocyte adhesion can be triggered by a variety of plasma components, such as interferon-gamma [16], homocysteine [17], and lipoproteins, like oxidized low density lipoprotein LDL (oxLDL) [18], or its derivates, oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine [19] and lysophosphatidylcholine [20].

          The identification of new plasma components which are responsible for monocyte adhesion is important in light of their potential application as pathogenic atherosclerosis markers, predictors, or therapeutic targets. Future studies may be focused on determining whether cLDL-induced adhesion results in increased rolling, arrest, and transmigration of monocytes [21].

References

  1.    Apostolov EO, Shah SV, Ok E, Basnakian AG. Carbamylated low-density lipoprotein induces monocyte adhesion to endothelial cells through intercellular adhesion molecule-1 and vascular cell adhesion molecule-1. Arterioscler Thromb Vasc Biol 2007Apr;27(4):826-32. Epub 2007 Jan 25.
  2.    Zhao SP, Xu DY. Oxidized lipoprotein(a) enhanced the expression of P-selectin in cultured human umbilical vein endothelial cells. Thromb Res 2000;100(6):501-10.
  3.    Rong R, Ramachandran S, Santanam N, Murphy AA, Parthasarathy S. Induction of monocyte chemotactic protein-1 in peritoneal mesothelial and endometrial cells by oxidized low-density lipoprotein and peritoneal fluid from women with endometriosis. Fertil Steril 2002;78(4):843-48.
  4.    Dwivedi A, Anggard EE, Carrier MJ. Oxidized LDL-mediated monocyte adhesion to endothelial cells does not involve NFkappaB. Biochem Biophys Res Commun 2001;284(1):239-44.
  5.    Kraus LM, Kraus AP, Jr. Carbamoylation of amino acids and proteins in uremia. Kidney Int Suppl 2001;78:S102-7.
  6.    Ok E, Basnakian AG, Apostolov EO, Barri YM, Shah SV. Carbamylated low-density lipoprotein induces death of endothelial cells: a link to atherosclerosis in patients with kidney disease. Kidney Int 2005;68(1):173-78.
  7.    Apostolov EO, Shah SV, Ok E, Basnakian AG. Quantification of carbamylated LDL in human sera by a new sandwich ELISA. Clin Chem 2005;51(4):719-28.
  8.    Apostolov EO, Basnakian AG, Yin X, Ok E, Shah S. Modified LDLs induce proliferation-mediated death of human vascular endothelial cells through the MAPK pathway. Am J Physiol Heart Circ Physiol 2007 Apr;292(4):H1836-46. Epub 2006 Dec 8.
  9.    O'Byrne D, Devaraj S, Islam KN, et al. Low-density lipoprotein (LDL)-induced monocyte-endothelial cell adhesion, soluble cell adhesion molecules, and autoantibodies to oxidized-LDL in chronic renal failure patients on dialysis therapy. Metabolism 2001;50(2):207-15.
  10.    Basnakian AG, Apostolov EO, Ok E, Yin X, Altunel E, Shah SV. Carbamylated LDL but not oxidized LDL is associated with atherosclerosis in uremic patients. Proceedings of the XLIII ERA-EDTA Congress, July 15-18, 2006, Glasgow, UK abstract #MP400, 2006.
  11.    Postea O, Krotz F, Henger A, Keller C, Weiss N. Stereospecific and redox-sensitive increase in monocyte adhesion to endothelial cells by homocysteine. Arterioscler Thromb Vasc Biol 2006;26(3):508-513.
  12.    Pae HO, Oh GS, Lee BS, Rim JS, Kim YM, Chung HT. 3-Hydroxyanthranilic acid, one of l-tryptophan metabolites, inhibits monocyte chemoattractant protein-1 secretion and vascular cell adhesion molecule-1 expression via heme oxygenase-1 induction in human umbilical vein endothelial cells. Atherosclerosis 2006;187(2):274-84.
  13.    Herold S, von Wulffen W, Steinmueller M, et al. Alveolar epithelial cells direct monocyte transepithelial migration upon influenza virus infection: impact of chemokines and adhesion molecules. J Immunol 2006;177(3):1817-24.
  14.    Erdogan A, Schaefer MB, Kuhlmann CR, et al. Activation of Ca(2+)-activated potassium channels is involved in lysophosphatidylcholine-induced monocyte adhesion to endothelial cells. Atherosclerosis 2007 Jan;190(1):100-5. Epub 2006 Apr 4.
  15.    Schleser S, Ringseis R, Eder K. Conjugated linoleic acids have no effect on TNFalpha-induced adhesion molecule expression, U937 monocyte adhesion, and chemokine release in human aortic endothelial cells. Atherosclerosis 2006;186(2):337-44.
  16.    Chang YJ, Holtzman MJ, Chen CC. Interferon-gamma-induced epithelial ICAM-1 expression and monocyte adhesion. Involvement of protein kinase C-dependent c-Src tyrosine kinase activation pathway. J Biol Chem 2002;277(9):7118-26.
  17.    Silverman MD, Tumuluri RJ, Davis M, Lopez G, Rosenbaum JT, Lelkes PI. Homocysteine upregulates vascular cell adhesion molecule-1 expression in cultured human aortic endothelial cells and enhances monocyte adhesion. Arterioscler Thromb Vasc Biol 2002;22(4):587-92.
  18.    Stewart BW, Nagarajan S. Recombinant CD36 inhibits oxLDL-induced ICAM-1-dependent monocyte adhesion. Mol Immunol 2006;43(3):255-67.
  19.    Hsiai TK, Cho SK, Reddy S, et al. Pulsatile flow regulates monocyte adhesion to oxidized lipid-induced endothelial cells. Arterioscler Thromb Vasc Biol 2001;21(11): 1770-76.
  20.    Kita T, Kume N, Ishii K, Horiuchi H, Arai H, Yokode M. Oxidized LDL and expression of monocyte adhesion molecules. Diabetes Res Clin Pract 1999;45(2-3):123-26.
  21.    Devaraj S, Davis B, Simon SI, Jialal I. CRP promotes monocyte-endothelial cell adhesion via Fc{gamma} receptors in human aortic endothelial cells under static and shear flow conditions. Am J Physiol Heart Circ Physiol 2006;291(3):H1170-76.

 

 

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