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O. Weingärtner, D. Lüthjohann, H.F. Schött, T. Speer, F.O. McCarthy, U. Laufs
Vascular effects of sterols, oxysterols, phytosterols, and oxyphytosterols in apoE-/-mice
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Objectives: Plant sterol esters (PSE) are used as food supplements to reduce serum cholesterol levels. Both plant sterols and cholesterol are prone to oxidation and convert to oxysterols and oxyphytosterols. The effects of oxysterols and oxyphytosterols on reactive oxygen species (ROS), endothelial function and atherogenesis in apoE-/-mice are not known. Methods: Male apoE-/-mice were subjected to intraperitoneal application of cholesterol, sitosterol, 7-beta-hydroxycholesterol, 7-beta-hydroxysitosterol or cyclodextrin solution as control over a time period of 4 weeks. After 4 weeks sterol, oxysterol, phytosterol and oxyphytosterol levels in serum were determined by gas chromatography-flame ionization or mass spectrometry, ROS production was assessed by electron-spin resonance (ESR) spectroscopy in aortic tissue and endothelial function of aortic rings and atherosclerosis in the aortic sinus was quantified (n=10 per group). Results: Compared to vehicle, i.p. application of cholesterol showed no difference in regard to plasma cholesterol levels (379±111 mg/dl vs. 381±41 mg/dl), but resulted in a decrease in lanosterol levels (156±54 vs. 118±6 μg/dl). Likewise, the i.p. application of 7-beta-hydroxy-cholesterol (0,0±0,0 vs. 0,196±0,094 mg/dl) and 7-beta-hydroxy-sitosterol (346±167 vs. 4899±1111 ng/ml) increased respective plasma levels compared to vehicle controls. However, this effect was not seen for sitosterol (40±27 vs.16±6 ng/ml). Electron-spin resonance (ESR) spectroscopy demonstrated that oxidative stress (ROS production) in the aorta was increased in 7-beta-hydoxy-sitosterol treated mice (increase compared to control by 157,7±48,9 %), but not in mice treated with cholesterol (91,9±67,5%), sitosterol (106,4±12,5%) or 7-beta-hydroxy-cholesterol (109,0±52,1%). Compared to controls, neither cholesterol nor sitosterol, or 7-beta- hydroxyl-cholesterol and 7-beta-hydroxy-sitosterol affected endothelium-dependent vasodilation. Atherosclerotic lesions were quantitated by oil-red-O-staining in the aortic sinus. Compared to controls there was no significant difference in mice treated with cholesterol (17,2±8,5 vs. 14,5±9,8 %), sitosterol (17,0±9,2 %), 7-beta-hydroxy-cholesterol (7,9±4,5 %) or 7-beta-hydroxy-sitosterol (10,1±6,4 %). Conclusion: Increased oxyphytosterol plasma concentrations were associated with increased ROS production in aortic tissue, but did not affect endothelial function or atherogenesis in apoE-/-mice.
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