Atherosclerosis oxysterols

Rat aorta control Atherosclerotic aorta human Atherosclerosis 1 +1 TOF-SIMS (MSI) Cholesterol, oxysterol, and diacylglycerols detected and localized (32)... 

Brown, A.J., Jessup, W. 1999. Oxysterols and atherosclerosis. Atherosclerosis 142, 1-28. Brown, A. J., Dean, R.T., Jessup, W. 1996. Free and esterified oxysterol formation during copper-oxidation of low-density lipoprotein and uptake of macrophage. J. Lipid Res. 37, 320-335. 

Lyons, M.A., Brown, A.J. 2000. Oxysterols in atherogenesis. In Atherosclerosis, Gene Expression, Cell Interactions, and Oxidation (R.T. Dean, D. Kelly, eds.), pp. 348-370, Oxford University Press, Oxford. 

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). 

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... 

Oxysterols arise from dietary sources, non-enzymatic oxidation, and enzymatic oxidation reactions [19]. The structure of some of the oxysterols that may be involved in atherosclerosis are shown in Fig. 5. Dietary oxysterols are incorporated into chylomicrons and... 

The proposed roles of oxysterols in atherosclerosis are based primarily on the results of cell-culture experiments. There are a number of in vivo studies in which investigators have exposed animals to oxysterols through diet or injection, but the overall results are not conclusive. For example, in a review by Brown and Jessup [19] of 13 oxysterol dietary studies, 6 showed an increase in atherosclerosis, but 4 demonstrated a decrease in lesion size and 3 showed no effect. Differences in animal models and types and doses of oxysterols undoubtedly account for some of these differences. 

Indeed, 27-hydroxycholesterol is a prominent oxysterol found in lesions. Rare patients lacking 27-hydroxylase activity have xanthomas and premature coronary artery disease, and some studies have shown an inverse correlation between 27-hydroxylase levels and atherosclerosis in subjects without enzyme deficiency per se (N.R. Cary, 2001). However, 27-hydroxylase-deficient mice on a non-atherogenic background or diet do not develop xanthomas or spontaneous atherosclerotic lesions (E. Leitersdorf, 1998). 

In summary, oxysterols are known to exist in atherosclerotic lesions and have been demonstrated in cell-culture experiments to have profound cellular effects that could influence the development, progression, and reversal of atherosclerosis. The key question in this field of research, however, is whether the concentrations of oxysterols in vivo are high enough to influence atherogenesis. Thus far, only the oxysterol-activated nuclear transcription pathway has been directly supported by in vivo data, and even in this case the precise roles and identification of the activating oxysterols in vivo have not yet been elucidated. Moreover, to the extent that oxysterols are generated in vivo and not just obtained from the diet, their role in human atherosclerosis has been questioned by clinical trials showing little or no protective effect of antioxidants on atherosclerotic coronary artery disease (K.J. Williams and E.A. Fisher, 2005). 

The second hypothesis deals with the construction heath profiles for early detection of coronary heart disease (CHD). This research involves relationships of oxysterols and DHEAS with the pathogenesis of atherosclerosis. 

The final component of the project involves correlating the analytical data with clinical information obtained by the contributing physicians. This could provide new insights regarding the role of oxysterols in the pathogenesis of atherosclerosis. Because specimens will be acquired from a variety of sources, a standardized format or questionnaire would be used to normalize the quality of the clinical information obtained from the different sources. 

Yasunobu, Y Hayashi, K. Shingu, T. Yamagata, T. Kajiyama, G. Kambe, M., Coronary atherosclerosis and oxidative stress as reflected by autoantibodies against oxidized low-density lipoprotein and oxysterols. Athewsclew 2001, 155(2), 445-53. 

Cholesterol oxidation products are undoubtedly among the lipid oxidation products that most likely contribute to the development of atherosclerotic lesions in human large- and medium-sized arteries. They are known collectively as oxysterols, and their importance stems not only from the quantitative impact of cholesterol and its esters on the lipid-metabolism-dependent effects on atherosclerosis, but also from the various significant biochemical properties exhibited by this class of compounds. 

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. 

Until very recently, research into the involvement of cholesterol oxidation products in the pathogenesis of atherosclerosis was mainly driven by the marked pro-inflammatory and pro-apoptotic effects that some members of this class of compounds exhibit (Poli et al. 2009 Vejux and Lizard 2009), whereas no attention was paid to possible anti-inflammatory or antiapoptotic signals generated by oxysterols. Nevertheless, an increased body of literature confirms the capability of oxysterols to interact with different nuclear receptors, which are known to play a main role in driving the anti-inflammatory and antiapoptotic cellnlar responses, thus suggesting a possible involvement of oxysterols even in these pathways. 

---