The role of oxysterols in control of endothelial stiffness

Tzu Pin Shentu, Dev K. Singh, Myung Jin Oh, Shan Sun, Laleh Sadaat, Ayako Makino, Theodore Mazzone, Papasani V. Subbaiah, Michael Cho, Irena Levitan

Research output: Contribution to journalArticle

29 Scopus citations

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. ox- LDL-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.

Original languageEnglish (US)
Pages (from-to)1348-1358
Number of pages11
JournalJournal of Lipid Research
Volume53
Issue number7
DOIs
StatePublished - Jul 1 2012
Externally publishedYes

Keywords

  • Atomic force microscopy
  • Cell stiffness
  • Cholesterol
  • Oxidized phosphatidylcholine

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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  • Cite this

    Shentu, T. P., Singh, D. K., Oh, M. J., Sun, S., Sadaat, L., Makino, A., Mazzone, T., Subbaiah, P. V., Cho, M., & Levitan, I. (2012). The role of oxysterols in control of endothelial stiffness. Journal of Lipid Research, 53(7), 1348-1358. https://doi.org/10.1194/jlr.M027102