Endothelial cells oxysterols

As mentioned earlier, oxidation of LDL is initiated by free radical attack at the diallylic positions of unsaturated fatty acids. For example, copper- or endothelial cell-initiated LDL oxidation resulted in a large formation of monohydroxy derivatives of linoleic and arachi-donic acids at the early stage of the reaction [175], During the reaction, the amount of these products is diminished, and monohydroxy derivatives of oleic acid appeared. Thus, monohydroxy derivatives of unsaturated acids are the major products of the oxidation of human LDL. Breuer et al. [176] measured cholesterol oxidation products (oxysterols) formed during copper- or soybean lipoxygenase-initiated LDL oxidation. They identified chlolcst-5-cnc-3(3, 4a-diol, cholest-5-ene-3(3, 4(3-diol, and cholestane-3 3, 5a, 6a-triol, which are present in human atherosclerotic plaques. 

Spyridopoulos, I., Wischhusen, J., Rabenstein, B., Mayer, P., Axel, D.L, Frohheh, K.U., and Karsch, K.R., 2001, Alcohol Errhances Oxysterol-lnduced Apoptosis in Human Endothelial Cells by a Caldum-Dependent Mechanism, Arterioscler. Thromb. Vase. Biol. 21 439 144. 

Ramasamy, S., Boissonneault, G.A., and Hennig, B., 1992, Oxysterol-induced endothelial cell dysfunction in culture, J. Am. Coll. Nutr. 11 532-538. 

There is experimental evidence that suggests that some oxysterols, but not pure cholesterol, are the prime cause of atherosclerotic lesion formation (162). Upon cholesterol feeding, a strong relationship was seen between plasma oxysterols and aortic wall oxysterols. One may speculate that the deposition of pure lipids, such as cholesterol and its esters, may be merely a secondary process in response to oxysterol-induced endothelial cell injury. Cell injury/dysfunction and the subsequent disruption of endothelial barrier function by oxysterols (163, 164) could initiate the early events in atherosclerosis. Such injury could allow increased uptake... 

D, Williams TA, Verhovez A, Bussolino F, Veglio F, Mulatero P (2009) LXR-activating oxysterols induce the expression of inflammatory markers in endothelial cells through LXR-independent mechanisms. 

Saint-Pol J, Candela P, Boucau MC, Fenart L, Gosselet F (2013) Oxysterols decrease apical -to-basolateral transport of Afi peptides via an ABCB1-mediated process in an in vitro Blood-brain barrier model constituted of bovine brain capillary endothelial cells. Brain Res 1517 1-15... 

Another important finding is that mmLDL contains mainly phospholipid oxidation products, while the oxysterol content increases proportionally with the oxidation rate (Shentu et al. 2012). Taken together, these very recent experimental reports and reviews suggest a primary role for oxysterols in the progression of atherosclerosis, rather than in its initiation. However, the marked biochemical changes that oxysterols have been found to bring about in endothelial cells (ECs) suggest that the possibility that cholesterol oxides make some contribution to endothelial dysfunction in atherosclerosis should not be discarded a priori. 

Li, W., M. Ghosh, S. Eftekhari, and X. M. Yuan. 2011. Lipid accumulation and lysosomal pathways contribute to dysfunction and apoptosis of human endothelial cells caused by 7-oxysterols. Biochem io l s es Cormjii i 409 (4) 711—6. 

FIGURE 3.8 Cholesterol has to be oxidized to leave the brain. Cholesterol cannot pass the blood-brain barrier. Hence, cholesterol in excess is oxidized into 24S-OH-cholesterol (A). The site of oxidation (C24) is indicated by an arrow. This transformation allows cholesterol to find its way through the plasma membranes of endothelial cells by inducing local deformations of the bilayer (B). Indeed, the s)mimetric OH groups of 24S-OH-cholesterol destabilize the bilayer, so that the oxysterol is gradually excluded from the membrane (red arrows). 

The oxysterol 7-ketocholesterol is an important COP involved in atherosclerotic lesions and macrophage foam cells (275). There is no direct evidence in humans that COPs contribute to atherogenesis, but it has been found that COP levels are elevated in LDL subfractions that are considered potentially atherogenic (276). In addition, raised levels of 7p-hydroxycholesterol may be associated with an increased risk of atherosclerosis. Arterial injury by COPs causes endothelial dysfunction and arterial wall cholesterol accumulation (277). Even under normocholesterolemic conditions, COPs can cause endothelial dysfunction, increased macromolecular permeability, and increased cholesterol accumulation. These are all factors believed to be involved in the development of atherosclerotic lesions. The atherogenic potential of COPs has been demonstrated by in vitro cell culture (73, 278), as well as in animal feeding studies (279). Japanese quail fed either purified cholesterol or oxidized cholesterol exhibited greater plasma and liver cholesterol concentrations in association with increased severity of atherosclerotic lesions when fed the oxidized cholesterol (279). 

FIGURE 15.4 Oxysterols may upregulate all steps in the transmigration of lenkocytes through the endothelial layer lining the arterial vessels. VCAM-1, vascular cell adhesion molecule-1 ICAM-1, intercellular adhesion molecule-1 MCP-1, monocyte chemotactic protein-1 MIP, monocyte inflammatory protein. 

---