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- W3004579791 abstract "Dyslipidemia, or abnormally high levels of blood cholesterol in the form of low-density lipoprotein (LDL), increases the chance of developing cardiovascular diseases, potentially leading to heart disease, diabetes, or stroke. Blood levels of oxidative modifications of low-density lipoprotein (oxLDL - a major proinflammatory and proatherogenic factor) are also increased under dyslipidemic conditions. In this study, we first performed mass spectrometric analyses of the sterol composition of human aortic endothelial cells (HAECs) exposed to the pathological levels of oxLDL observed in hypercholesterolemia in vivo. We found that exposure of HAECs to oxLDL does not lead to an increase in cellular cholesterol, but results instead in significant incorporation of oxysterols, particularly, 7-ketocholesterol. In this study, we computationally investigate the impact of the physiological increases of 7-ketocholesterol on the physical properties of endothelial membranes using coarse-grained molecular dynamics simulations to compare dyslipidemic lipid compositions to normal physiological profiles. A topology of 7-ketocholesterol based on the Martini coarse-graining scheme was created, validated, and subsequently incorporated into multi-component lipid bilayers representing endothelial membranes at both physiological and dyslipidemic concentrations, determined by mass spectrometric analyses. Molecular simulations show differential membrane perturbation effects of the various concentrations of oxidized sterol present, including increased fluidization and decreased packing of the membrane lipids accompanying increased 7-ketocholesterol levels, effects contrary to those expected to be caused by non-oxidized cholesterol. Differences in sterol diffusion rates, water, and lipid distribution within the model membranes were also observed. These changes in membrane structure and dynamics in response to varying levels of 7-ketocholesterol would suggest that, in addition to altering lipid composition, dyslipidemic conditions involving this oxidized sterol, along with several other bioactive molecules, disrupt the biomechanical integrity of the endothelial membrane." @default.
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- W3004579791 date "2020-02-01" @default.
- W3004579791 modified "2023-10-18" @default.
- W3004579791 title "Impact of Dyslipidemic Levels of Oxidized Cholesterol on Endothelial Membranes" @default.
- W3004579791 doi "https://doi.org/10.1016/j.bpj.2019.11.1131" @default.
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