Carbamylated Low-Density Lipoprotein Induces Monocyte Adhesion to Endothelial Cells Through Intercellular Adhesion Molecule-1 and Vascular Cell Adhesion Molecule-1

Abstract

Objective-Carbamylated low-density lipoprotein (LDL), the most abundant modified LDL isoform in human blood, has been recently implicated in causing the atherosclerosis-prone injuries to endothelial cells in vitro and atherosclerosis in humans. This study was aimed at testing the hypothesis that carbamylated LDL acts via inducing monocyte adhesion to endothelial cells and determining the adhesion molecules responsible for the recruitment of monocytes. Methods and Results-Exposure of human coronary artery endothelial cells with carbamylated LDL but not native LDL caused U937 monocyte adhesion and the induction of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 adhesion molecules as measured by cell enzyme-linked immunosorbent assay. Silencing of intercellular adhesion molecule-1 by siRNA or its inhibition using neutralizing antibody resulted in decreased monocyte adhesion to the endothelial cells. Similar silencing or neutralizing of vascular cell adhesion molecule-1 alone did not have an effect but was shown to contribute to intercellular adhesion molecule-1 when tested simultaneously. 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 3 main families of receptors: members of the immunoglobulin superfamily, selectins, and integrins. Recent studies indicate that intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), members of the immunoglobulin superfamily, are the most common participants in monocyte attraction induced by different stimuli. [1][2][3] The expression of adhesion molecules and monocyte adhesion can be triggered by a variety of plasma components, such as interferon-␥, 4 homocysteine, 5 and lipoproteins, like oxidized low-density lipoprotein (oxLDL), 6 or its derivates, oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine 7 and lysophosphatidylcholine. 8 The identification of new plasma components that are responsible for monocyte adhesion is important in light of their potential application as pathogenic atherosclerosis markers, predictors or therapeutic targets. Conclusions-TakenCarbamylated low-density lipoprotein (cLDL) is a recently identified type of modified low-density lipoprotein (LDL) that seems to be important in atherosclerosis in humans. 9 -11 It is generated by irreversible chemical modification of the protein component of the LDL particle, apolipoprotein B, and by urea-derived cyanate present in human blood plasma. 9 Plasma levels of cLDL as determined by sandwich enzymelinked immunosorbent assay (ELISA) methods vary in a higher range of concentrations than oxLDL, which makes it the most abundant LDL isoform of human plasma. 11 The elevation of blood urea in uremic patients causes a proportional increase of plasma cLDL. 11 The LDL of chronic renal failure patients on dialysis was shown to induce g...

Chronic Uremia Stimulates LDL Carbamylation and Atherosclerosis

“…Our previous data established strong links between cLDL, expression of ICAM-1, and monocyte adhesion and showed that ICAM-1 is more relevant to cLDL than to other LDLs. 13 Therefore, our current in vivo data confirm our previous results obtained in vitro and verify that ICAM-1 is involved in cLDL atherogenesis. In conclusion, our findings provide initial in vivo evidence to implicate cLDL resulted from elevated urea as an independent pathogenic factor for uremiainduced atherosclerosis.…”

“…9,[13][14][15][16] Among those, the role of the intercellular adhesion molecule 1 (ICAM-1) and monocyte adhesion by endothelium were most prominent and, in some conditions, exceeded those induced by oxLDL. 13 To test whether ICAM-1 overexpression and macrophage housing occurred in vivo as a result of uremic atherosclerosis associated with LDL carbamylation, the aortic samples were simultaneously stained for cLDL and for ICAM-1 or CD68, respectively. Our data showed that ICAM-1 protein expression was significantly higher in CRF and ϩUC mice fed HFD compared with all controls ( Figure 4B).…”

“…An alternative myeloperoxidase-mediated mechanism of LDL carbamylation has been suggested by Wang et al, 12 who also observed a correlation between total plasma protein carbamylation and the incidence of cardiovascular disease in nonuremic patients. cLDL promotes several biologic processes in vitro that are regarded as pro-atherogenic, including vascular smooth muscle cell proliferation, monocyte adhesion to endothelial cells, 13,14 and endothelial cell cytotoxicity. 9,15,16 However, experimental evidence showing a pro-atherogenic effect of cLDL in vivo is lacking.…”

Carbamylation-Derived Products: Bioactive Compounds and Potential Biomarkers in Chronic Renal Failure and Atherosclerosis

“…In addition, macrophage scavenger receptors recognize cLDLs (17,49 ). cLDLs have been reported to promote the adhesion of monocytes on endothelial cells (50 ), induce endothelial cell death (51,52 ), stimulate the proliferation of vascular smooth muscle cells (53 ), and induce oxidative stress and accelerated senescence in human endothelial progenitor cells (54 ). Carbamylated HDLs have been reported to contribute to the atherosclerotic process by promoting foam cell formation (55 ).…”

Cytotoxic Endonucleases: New Targets for Prostate Cancer Chemotherapy

“…This report suggests the presence of EndoG in non-invasive breast cancer cells determines their sensitivity to apoptosis, which may be taken into consideration for developing the chemotherapeutic strategy for cancer treatment. In other cells, EndoG has been recognized as a key endonuclease in the caspase-independent apoptosis (Abbott et al, 2001;Bahi et al, 2006), mitotic catastrophe (Diener et al, ;Wang et al, 2008), and necrosis (Apostolov et al, 2007a;Jiang et al, 2006). Because anticancer drugs induce apoptosis in cancer cells through endonuclease-mediated DNA fragmentation (Ploski & Aplan, 2001;Shrivastava et al, 2000), and the inhibition of endonucleases has a protective effect (Shrivastava et al, 2000), endonuclease should be considered as important mediators of cancer cell death and potential therapeutic targets for www.intechopen.com the anticancer therapy.…”