Selective distribution of oxysterols in atherosclerotic lesions and human plasma lipoproteins

Abstract

The presence of oxidized sterols (oxysterols) in human serum and lesions has been linked to the initiation and progression of atherosclerosis. Data concerning the origin, identity and quantity of oxysterols in biological samples are controversial and inconsistent. This inconsistency may arise from different analytical methods or handling conditions used by different investigators. In the present study, oxysterol levels and distribution were analyzed by an optimized GC-MS method, in human atherosclerotic coronary and carotid lesions, in atherosclerotic apolipoprotein E deficient mice (E degrees mice) and in native and in vitro oxidized human low and high density lipoproteins. Oxysterol levels were analyzed with a limit of detection of 0.06 - 0.24 ng, with 25-hydroxycholesterol (25-OH) being the least sensitive. In human coronary and carotid lesions, obtained from endatherectomic samples, 27-hydroxycholesterol (27-OH) was the major oxysterol, with about 85% as sterols esterified to fatty acids. While total cholesterol and oxysterols levels were similar in both kinds of human lesions, oxysterol distribution was significantly different. In coronary lesions the mean levels of 27-OH and 7beta-hydroxycholesterol (7beta-OH) were 38% and 20% of total oxysterols, whereas in carotid lesions their mean levels were 66% and 5%, respectively. Unlike in human aortic lesions, 27-OH was entirely absent in E degrees mice, whereas the level of 7alpha-hydroxycholesterol (7alpha-OH) was 28% of the total oxysterols, vs. 5% in human coronary lesions. As 27-OH is an enzymatic product of cholesterol oxidation, this finding may indicate that such an enzymatic process does not take place in E degrees mice.

The role of oxysterols in control of endothelial stiffness

“…Furthermore, we found a striking correlation between an increase in endothelial stiffness and the amount of oxysterols in oxLDL. These observations are consistent with strongly oxidized LDL having more impact on endothelial stiffness compared with mmLDL, because although In terms of the presence of oxysterols in vivo, earlier studies have shown that oxysterols are found in vascular tissues of ApoE Ϫ / Ϫ mice with advanced atherosclerosis, as well as in human atherosclerotic lesions ( 25,65 ). Our studies show that a signifi cant accumulation of oxysterols was found in aortic tissue of male ApoE Ϫ / Ϫ mice fed a low-cholesterol chow diet at a very early stage of disease progression (10-12 weeks of age) when typically no foam cell lesions are observed ( 52 ).…”

Oxidized cholesterol in the diet is a source of oxidized lipoproteins in human serum

“…Given these results in animal models, it is likely that oxidized cholesterol in the diet would also accelerate atherosclerosis in humans. In fact, oxidized cholesterol is found in human foam cells and advanced atherosclerotic lesions (30,31). In individuals with atherosclerosis, plasma levels of oxidized cholesterol appear to be higher than in healthy controls (50), and coronary atherosclerosis is reflected by autoantibodies against oxidized LDL and oxidized cholesterol in the serum (51).…”

“…It was purchased from Steraloids Inc. (Newport, RI), and was selected because it is one of the major oxidized cholesterol components in heated or stored foods (10)(11)(12)(13). It has also been detected in human serum (27)(28)(29) and atherosclerotic lesions (30,31). It is efficiently absorbed as indicated by studies with experimental animals (19).…”

Ezetimibe inhibits the incorporation of dietary oxidized cholesterol into lipoproteins

“…There are considerable data demonstrating that lipoproteins are oxidized locally in the intima of the arterial wall (1-4) as well as evidence that oxidized lipoproteins are present in human serum (5,6). These circulating oxidized lipoproteins can be taken up by the arterial wall and thereby contribute to the levels of oxidized lipoproteins in the intima.…”