OxLDL

It is accepted that oxidation of LDL is a key event in endothelial injury and dysfunction. Oxidised LDL (oxLDL) may directly injure the endothelium and trigger the expression of migration and adhesion molecules. Monocytes and lymphocytes interact with oxLDL and the phagocytosis which follows leads to the formation of foam cells, which in turn are associated with the alteration of the expression pattern of growth regulatory molecules, cytokines and pro-inflammatory signals. The proposed role of oxLDL in atherogenesis, based on studies in vitro, is shown in Fig. 2.1. 

Fig. 2.1 Sequence of events in atherogenesis and role of low-density lipoprotein. Native LDL, in the subendothelial space, undergoes progressive oxidation (mmLDL) and activates the expression of MCP-1 and M-CSF in the endothelium (EC). MCP-1 and M-CSF promote the entry and maturation of monocytes to macrophages, which further oxidise LDL (oxLDL). Ox-LDL is specifically recognised by the scavenger receptor of macrophages and, once internalised, formation of foam cells occurs. Both mmLDL and oxLDL induce endothelial dysfunction, associated with changes of the adhesiveness to leukoc)des or platelets and to wall permeability.

IkB inhibitory protein kappa B lCAM-1 intercellular adhesion molecule 1 lL-1 interleukin-1 LDL low density lipoprotein MAPKs mitogen activated protein kinases MCP-1 macrophage chemotactic protein 1 M-CSF macrophage colony stimulating factor mmLDL minimally modified LDL NAC A-acetylcysteine NF-kB nuclear factor-kappa B oxLDL oxidised LDL PKC protein kinase C PMA phobol myristate acetate ROS reactive oxygen species TNF-a tumour necrosis factor alpha AM-1 vascular cell adhesion molecule 1... 

Baird, S.K. et al., OxLDL induced cell death is inhibited by the macrophage synthesised pterin, 7,8-dihydroneopterin, in U937 cells but not THP-1 cells, Biochim. Biophys. Acta 1745, 361, 2005. 

Apo E, apolipoprotein E CAD, coronary artery disease FKN, fractalkine MHC, major histocompatibility complex MCP-1, monocyte chemoattractant protein 1 MMPs, matrix metalloproteinases NK, natural killer oxLDL, oxidized LDL RANTES, regulated on activation, normal T cell expressed and secreted VSMCs, vascular smooth muscle cells. 

Increased in atherosclerotic lesions in high-fat-fed Apo E knockout mice. 2. IFN-y-dependent CXCL6 upregulation leads to increased oxLDL uptake in macrophages. Increased levels in human atherosclerotic lesions. 

Fig. 11.1. Atherogenesis is a persistent inflammatory response that occurs in response to conditions that cause endothelial damage (e.g., hypercholesterolemia and oxLDL). After endothelial cells are activated, they elaborate cytokines, chemokines, and other mediators that recruit mononuclear cells (monocytes and T lymphocytes) to extravasate into the vessel wall where they are activated and release additional proinflammatory factors. Macrophages are able to take up oxLDL via scavenger receptors causing them to differentiate into foam cells and form a fatty streak that progresses to an atheroma with a necrotic lipid core and a fibrous cap. Chemokines can lead to weakening of the fibrous cap and eventual plaque rupture leading to thrombosis and occlusion of the involved vessel.

Calvo, D, Gomez-Coronado, D, Lasuncion, MA, and Vega, MA, 1997. CLA-1 is an 85-kD plasma membrane glycoprotein that acts as a high-affinity receptor for both native (HDL, LDL, and VLDL) and modified (OxLDL and AcLDL) lipoproteins. Arterioscler Thromb Vase Biol 17, 2341-2349. 

Gordiyenko, N, Campos, M, Lee, JW, Fariss, RN, Sztein, J, and Rodriguez, IR, 2004. RPE cells internalize low-density lipoprotein (LDL) and oxidized LDL (oxLDL) in large quantities in vitro and in vivo. Invest Ophthalmol Vis Sci 45, 2822-2829. 

The pathophysiological role of oxidized LDL-induced apoptosis in vessel wall homeostasis is complex and probably depends on the cell type that oxLDL interacts with. For instance, EC are potential early targets, oxidized LDL may alter their functions and lead to apoptosis, contributing to early... 

Numerous experiments have suggested that LDL oxidation generates determinants that lead to a specific immune response that, together with the innate immune response, acts as an oxLDL clearance mechanism (Fignre lA) (Horkko etal, 2000 Shaw etal, 2000). 

A- The immune system participates in tissue homeostasis by the elimination of oxLDL and infectious agents, and consequently by the decrease of vascular ceil death. 

B Chronic hyperlipidemia and chronic infection potentiate inflammation and lipid oxidation. An increase of lipid oxidation might inhibit tbe immune system and thus facilitate a chronic infection and a rise in oxLDL-mediated apoptosis. 

Figure 1. Hypothetical interactions between infectious agents, oxLDL and the immune system in atherogenesis.

In summary, the binding of oxLDL and/or lipids to several SC receptors (SRAI/II, CD36, CD68) has been clearly demonstrated. Most of other receptors may potentially bind oxLDL or lipids. Consequently, the cellular internalization of oxidized lipids by the SC receptor pathways may be involved in the biological effect of oxLDL, such as apoptosis induction. As a likely major ligand and because of their oxidized lipid contents, oxLDL may have many putative effects on different cells, such as alteration of cell signaling and gene expression. 

Whatever the pathway for oxLDL uptake, numerous observations have demonstrated that their oxidized lipid contents can be directly toxic for the... 

The contribution of oxysterols to the cytotoxicity of oxidized LDL is likely, but it is to be noted that oxysterol concentrations necessary to trigger apoptosis in cultured cells are much higher than that reported in toxic concentrations of oxidized LDL and in atherosclerotic plaques (Brown and Jessup, 1999). This could be due to a synergistic effect of the different toxic molecules brought by the oxLDL. 

Intracellular events during oxLDL-induced apoptosis... 

Brigehus-Flohe,R., Maurer, S., Lotzer, K., Bol, G., Kalhonpaa, H., Lehtolainen, P., Viita, H., and Yla-Herttuala, S., 2000, Overexpression ofPHGPx inhibits hydroperoxide-induced oxidation, NFkappaB activation and apoptosis and affects oxLDL-mediated proliferation of rabbit aortic smooth muscle cells, Atherosclerosis 152 307-316. 

Li, D., Yang, B., and Mehta, J.L., 1998a, OxLDL induces apoptosis in human coronary endothelial cells role of PKC, PTK, bcl-2, and Fas, Am. J. Physiol. 275 H568-576. 

Li, W., Yuan, X.M., Brunk, U.T., 1998b, OxLDL-induced macrophage cytotoxicity is mediated by lysosomal rupture and modified by intralysosomal redox-active iron, Free Radio. Res. 29 389-398. 

Blood vessels Endothelia Tumour vasculature Lactoferrin, OxLDL Anti-VEGF-R Ab, VEGF Rat Atherosclerosis Solid tumours... 

Ab, Antibody BBB, Blood Brain Barrier CNS, Central Nervous System HIV, Human Immunodeficiency Virus HSA, Human Serum Albumin IGF, Insulin Growth Factor I/R, Ischaemia/Reperfusion MW, Molecular Weight OxLDL, Oxidized Low Density Lipoprotein -R, -receptor sCD4, soluble CD4 VEGF, Vascular Endothelial Growth Factor. 

Fig. 14.1 Foam cells obtained after addition of oxLDL, incubated with adenosine in the absence and in the presence of A3 adenosine receptor antagonist (Oil red O staining)...

Shatrov VA, Sumbayev W, Zhou J, Brtine B (2003) Oxidized low-density lipoprotein (oxLDL) triggers hypoxia-inducible factor-lalpha (HIF-lalpha) accumulation via redox-dependent mechanisms. Blood 101(12) 4847-9... 

---