Minimally modified LDL

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... 

RAJAVASHISTH T B, YAMADA H and MiSHRA N K (1995) Transcriptional activation of macrophage stimulating factor gene by minimally modified LDL Arteriosclerosis, Thrombosis and Vascular Biology 15, 1591-8. 

LOX-catalyzed oxidation of LDL has been studied in subsequent studies [26,27]. Belkner et al. [27] showed that LOX-catalyzed LDL oxidation was not restricted to the oxidation of lipids but also resulted in the cooxidative modification of apoproteins. It is known that LOX-catalyzed LDL oxidation is regio- and enantio-specific as opposed to free radical-mediated lipid peroxidation. In accord with this proposal Yamashita et al. [28] showed that LDL oxidation by 15-LOX from rabbit reticulocytes formed hydroperoxides of phosphatidylcholine and cholesteryl esters regio-, stereo-, and enantio-specifically. Sigari et al. [29] demonstrated that fibroblasts with overexpressed 15-LOX produced bioactive minimally modified LDL, which is probably responsible for LDL atherogenic effect in vivo. Ezaki et al. [30] found that the incubation of LDL with 15-LOX-overexpressed fibroblasts resulted in a sharp increase in the cholesteryl ester hydroperoxide level and a lesser increase in free fatty acid hydroperoxides. 

Miller YI, Viriyakosol S, Binder CJ, et al. (2(X)3b) Minimally modified LDL binds to CD 14, induces macrophage spreading via TLR4/MD-2, and inhibits phagocytosis of apoptotic cells. J Biol Chem 278 1561-1568... 

Fig. 7. Oxidation of LDL phospholipids in the generation of minimally modified LDL. Seeding molecules like HPETE, HPODE, and cholesteryl linoleate hydroperoxide (CE-OOH) are proposed to trigger the oxidation of l-palmitoyl-2-arachidonoyl phosphatidylcholine in LDL, leading to the generation of three oxidized phosphatidylcholine species that confer atherogenic activity to minimally modified LDL. 12-LO, 12-lipoxygenase. Adapted from Ref. [28]. Reproduced with permission from the publisher.

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.

Several studies have shown that TLR4 and/or TLR2 are involved in the recognition of oxLDL and minimally modified LDL resulting in promotion of inflammatory... 

M-CSF macrophage colony-stimulating factor mmLDL minimally modified LDL... 

Bork, R. W., Svenson, K. L., Mehrabian, M., Lusis, A. J., Fogelman, A. M., and Edwards, P.A. (1992) Mechanisms controlling competence gene expression in murine fibroblasts stimulated with minimally modified LDL. Arterioscler. Thromb. 12,800-806. 

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