title: The role of oxysterols in control of endothelial stiffness.
abstract: Endothelial dysfunction is a key step in atherosclerosis development. Our recent studies suggested that oxLDL-induced increase in endothelial stiffness plays a major role in dyslipidemia-induced endothelial dysfunction. In this study, we identify oxysterols, as the major component of oxLDL, responsible for the increase in endothelial stiffness. Using Atomic Force Microscopy to measure endothelial elastic modulus, we show that endothelial stiffness increases with progressive oxidation of LDL and that the two lipid fractions that contribute to endothelial stiffening are oxysterols and oxidized phosphatidylcholines, with oxysterols having the dominant effect. Furthermore, endothelial elastic modulus increases as a linear function of oxysterol content of oxLDL. Specific oxysterols, however, have differential effects on endothelial stiffness with 7-ketocholesterol and 7α-hydroxycholesterol, the two major oxysterols in oxLDL, having the strongest effects. 27-hydroxycholesterol, found in atherosclerotic lesions, also induces endothelial stiffening. For all oxysterols, endothelial stiffening is reversible by enriching the cells with cholesterol. oxLDL-induced stiffening is accompanied by incorporation of oxysterols into endothelial cells. We find significant accumulation of three oxysterols, 7α-hydroxycholesterol, 7β-hydroxycholesterol, and 7-ketocholesterol, in mouse aortas of dyslipidemic ApoE⁻/⁻ mice at the early stage of atherosclerosis. Remarkably, these are the same oxysterols we have identified to induce endothelial stiffening.
authors.affiliation: Pulmonary, Critical Care, and Sleep Medicine, University of Illinois, Chicago, IL 60612, USA.
authors.forename: Tzu Pin
authors.initials: TP
authors.lastname: Shentu
authors.forename: Dev K
authors.initials: DK
authors.lastname: Singh
authors.forename: Myung-Jin
authors.initials: MJ
authors.lastname: Oh
authors.forename: Shan
authors.initials: S
authors.lastname: Sun
authors.forename: Laleh
authors.initials: L
authors.lastname: Sadaat
authors.forename: Ayako
authors.initials: A
authors.lastname: Makino
authors.forename: Theodore
authors.initials: T
authors.lastname: Mazzone
authors.forename: Papasani V
authors.initials: PV
authors.lastname: Subbaiah
authors.forename: Michael
authors.initials: M
authors.lastname: Cho
authors.forename: Irena
authors.initials: I
authors.lastname: Levitan
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008077:Lipoproteins, LDL / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013261:Sterols / Q000032:analysis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D001057:Apolipoproteins E; D008077:Lipoproteins, LDL; D013261:Sterols; C099252:oxidized low density lipoprotein