Endothelial cells oxLDL

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.

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. 

Other proatherogenic effects of OxLDL and oxphospholipids include the ability to attract monocytes, to inhibit the motility of macrophages, to prevent the release of vasodilatory nitric oxide (NO) from endothelial cells,... 

Fig. 1. Oxidation hypothesis. Proposes minimally modified LDL is formed due to oxidation in the arterial intimal space. This LDL can still be taken up by the LDL receptor, but minimally modified LDL promotes release of proinflammatory mediators from monocytes and acts as a monocyte inhibition factor (MIF), reducing the motility of monocytes and thus leading to recruitment of macrophages (J4, W9). Macrophages further oxidize LDL (OxLDL), release inflammatory mediators, and rapidly take up OxLDL and other lipoproteins via the unregulated scavenger receptor that binds modified apo B to form lipid-laden foam cells. OxLDL is cytotoxic to a variety of cells in culture and may disrupt endothelial tissue, causing the release of inflammatory mediators and the entry of more LDL into the intimal space. Continued accumulation of monocytes and their differentiation into macrophages leads to a vicious cycle (J4, W9). Adapted from reference J4.

Effect on ROS-mediated events Leucocyte adhesion to endothelial cells provoked by oxLDL FO Hamster Reference (38)... 

Morawietz H, Duerrschmidt N, Niemann B, Galle J, Sawamura T, Holtz J. Induction of the oxLDL receptor LOX-1 by endothelin-1 in human endothelial cells. and Biophysical Research Communications 2001 284 961-965. 

In human arterial endothelial cells, L-ascorbic acid, alone or in combination with a-tocopherol-induced proliferation and DNA synthesis and antagonized the antiproliferative effects of oxLDL, bnt in VSMC the proliferation is inhibited (Ulrich-Merzenich et al. 2002). The ECM may contribute to the inhibition of DNA synthesis and proliferation, since VSMC plated on extracellular matrices deposited by VSMC in the presence of 0.1-1 mM L-ascorbic acid had an up to 50% lower proliferation rate than on matrices from L-ascorbic acid-deficient cells (Ivanov et al. 1997). The inhibitory effect is not specific for the biological active isomer of L-ascorbic acid, and isoascorbate and D-ascorbic acid are even more effective in reducing cell growth than L-ascorbic acid (Alcain and Buron 1994). 

There is considerable evidence that inflammatory response induced by oxidized low-density lipoprotein (oxLDL) contribute to the development of atherosclerosis. OxLDL or their metabolites have been found in atherosclerotic lesions in both human and animal models (i). OxLDLs have been shown to stimulate endothelial cells to express several proteins that contribute to atherosclerosis, including monocyte chemotactic protein-1 (MCP-1),... 

Investigators have shown that a decrease in the release of tissue plasminogen activator (tPA) and an elevation of plasminogen activator inhibitor 1 (PAI-1) will reduce fibrinolytic function. It has emerged that triacylglycerol-rich lipoproteins stimulate PAI-1 secretion from endothelial cells, and furthermore it has been shown that OxLDL induces secretion, whereas native LDL has no detectable... 

Hoffmann, J., Haendeler, J., Zeiher, A.M., and Dimmeler, S. (2001). TNFalpha and oxLDL reduce protein S-nitrosylation in endothelial cells. J. Biol. Chem. 276,41383-41387. 

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.

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