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Oxysterols, cholesterol biosynthesis, and vascular endothelial cell monolayer barrier function
G A Boissonneault1, B Hennig, C M Ouyang
1Department of Clinical Sciences, University of Kentucky, Lexington 40536.
Abstract:
A spectrum of cholesterol oxidation derivatives (oxysterols) is generated in food products exposed to heat or radiation in the presence of oxygen. One of these derivatives (cholestan-3 beta,5 alpha,6 beta-triol) was shown to compromise the selective barrier function of cultured vascular endothelial cell monolayers, an action that may initiate atherosclerotic lesion formation. This study sought to investigate the relationship of cholesterol synthesis inhibition by several naturally occurring oxysterols to depression of vascular endothelial cell monolayer barrier function, determined as an increase in albumin transfer across cultured endothelial monolayers. All oxysterols tested caused a variable time- and dose-dependent elevation in trans-endothelial albumin transfer, and they were also able to inhibit cholesterol biosynthesis to varying degrees. Pure cholesterol was without effect on both counts. The correlation between the increase in albumin transfer related to oxysterol exposure and the ability of oxysterols to suppress cholesterol biosynthesis was, however, poor. Moreover, mevinolin, a water-soluble competitive inhibitor of cholesterol synthesis, reduced the rate of cholesterol synthesis to 0.9% of control but did not significantly increase albumin transfer. Cholestan-3 beta,5 alpha,6 beta-triol caused a 660% elevation in albumin transfer while cholesterol synthesis remained at 11% of control. We conclude that changes in endothelial barrier function caused by exposure to the oxysterols examined, but not pure cholesterol, are probably related to factors other than the well-known action of cholesterol biosynthesis inhibition. These findings may have implications in the development of atherosclerosis.
Insights
Oxysterols, cholesterol oxidation products, disrupt endothelial barrier function and may contribute to atherosclerosis. Their effects on barrier function are likely independent of cholesterol synthesis inhibition.
Area of Science:
- Biochemistry
- Cardiovascular Biology
- Cell Biology
Background:
- Oxysterols are cholesterol oxidation derivatives found in foods.
- Certain oxysterols can compromise vascular endothelial cell barrier function.
- This compromise may play a role in the initiation of atherosclerotic lesion formation.
Purpose of the Study:
- To investigate the relationship between cholesterol synthesis inhibition by oxysterols and their effect on endothelial barrier function.
- To determine if oxysterol-induced changes in barrier function correlate with suppressed cholesterol biosynthesis.
- To explore the mechanisms by which oxysterols impact endothelial cells.
Main Methods:
- Exposure of cultured vascular endothelial cell monolayers to various oxysterols and pure cholesterol.
- Measurement of trans-endothelial albumin transfer to assess barrier function.
- Quantification of cholesterol biosynthesis inhibition by oxysterols and mevinolin.
Main Results:
- All tested oxysterols increased albumin transfer and inhibited cholesterol biosynthesis in a dose- and time-dependent manner.
- Pure cholesterol had no effect on barrier function or cholesterol biosynthesis.
- A poor correlation was observed between increased albumin transfer and cholesterol biosynthesis inhibition.
- Mevinolin significantly inhibited cholesterol synthesis but did not increase albumin transfer.
- Cholestan-3 beta,5 alpha,6 beta-triol markedly elevated albumin transfer while only partially inhibiting cholesterol synthesis.
Conclusions:
- Oxysterol-induced changes in endothelial barrier function are likely mediated by mechanisms other than cholesterol biosynthesis inhibition.
- Pure cholesterol does not affect endothelial barrier function or cholesterol synthesis.
- These findings suggest novel pathways involved in atherosclerosis development related to oxysterol exposure.