@article{064d1a65cdad4c15801370c910957a95,
title = "Cyclodextrin promotes atherosclerosis regression via macrophage reprogramming",
abstract = "Atherosclerosis is an inflammatory disease linked to elevated blood cholesterol concentrations. Despite ongoing advances in the prevention and treatment of atherosclerosis, cardiovascular disease remains the leading cause of death worldwide. Continuous retention of apolipoprotein B-containing lipoproteins in the subendothelial space causes a local overabundance of free cholesterol. Because cholesterol accumulation and deposition of cholesterol crystals (CCs) trigger a complex inflammatory response, we tested the efficacy of the cyclic oligosaccharide 2-hydroxypropyl-β-cyclodextrin (CD), a compound that increases cholesterol solubility in preventing and reversing atherosclerosis. We showed that CD treatment of murine atherosclerosis reduced atherosclerotic plaque size and CC load and promoted plaque regression even with a continued cholesterol-rich diet. Mechanistically, CD increased oxysterol production in both macrophages and human atherosclerotic plaques and promoted liver X receptor (LXR)- mediated transcriptional reprogramming to improve cholesterol efflux and exert anti-inflammatory effects. In vivo, this CD-mediated LXR agonism was required for the antiatherosclerotic and anti-inflammatory effects of CD as well as for augmented reverse cholesterol transport. Because CD treatment in humans is safe and CD beneficially affects key mechanisms of atherogenesis, it may therefore be used clinically to prevent or treat human atherosclerosis.",
author = "Sebastian Zimmer and Alena Grebe and Bakke, {Siril S.} and Niklas Bode and Bente Halvorsen and Thomas Ulas and Mona Skjelland and {De Nardo}, Dominic and Labzin, {Larisa I.} and Anja Kerksiek and Chris Hempel and Heneka, {Michael T.} and Victoria Hawxhurst and Fitzgerald, {Michael L.} and Jonel Trebicka and Ingemar Bj{\"o}rkhem and Gustafsson, {Jan {\AA}ke} and Marit Westerterp and Tall, {Alan R.} and Wright, {Samuel D.} and Terje Espevik and Schultze, {Joachim L.} and Georg Nickenig and Dieter L{\"u}tjohann and Eicke Latz",
note = "Funding Information: Acknowledgments: We appreciate the great technical assistance of C. Lahrmann, A. Glubokovskih, G. Hack and S. Bellinghausen (University of Bonn), A. Marstad (Norwegian University of Science and Technology), Z. Ali (Karolinska Institutet), and K. Krohg-S{\o}rensen (Oslo University Hospital). We thank C. Hastings (Children's Hospital & Research Center Oakland) for help with the acquisition of samples from NPC patients and greatly appreciate the contribution of the Hadley Hope Fund (Medford). CD and rhodamine-labeled CD were provided by CTD Holdings Inc. LD540 was provided by C. Thiele (University of Bonn). Funding: This work wasfunded by NIH grants R01-HL093262, R21-HL113907-01 (to E.L.), HL112661-01 (to M.LF. and E.L.), HL101274 (to M.L.F.), and HL107653 (to A.R.T.); the Research Council of Norway through its Centres of Excellence funding scheme project no. 223255/F50 (to S.S.B., E.L, and T.E.); BONFOR (to S.Z. and N.B.); the Robert A. Welch Foundation (E-0004;to J.-{\AA}.G.);the Swedish Science Council (H2416223; to J.-{\AA}.G.); and grants from the Deutsche Forschungsgemeinschaft (DFG; SFB645, SFB670, SFB704, TRR83, and TRR57) (to E.L., J.L.S., and J.T.). E.L, M.T.H., and J.L.S. are members of the Excellence Cluster ImmunoSensation (Exc1023) funded by the DFG. Author contributions: S.Z. and A.G. designed, performed, and analyzed experiments. N.B. assisted with atherosclerosis mouse models and data analysis. S.S.B., L.I.L, B.H., M.S., J.T., A.K., and V.H. performed experiments. S.S.B., T.U., and J.L.S. performed bioinformatic analyses. J.-{\AA}.G., M.T.H., I.B., M.W., and A.R.T. provided knockout mice. D.D., G.N., T.E., M.L.F., S.D.W., and D.L. analyzed data and provided critical suggestions and discussions throughout the study. C.H. provided the initial idea for the study. S.Z., A.G., and E.L. designed the study and wrote the manuscript. Competing interests: S.D.W. is a full-time employee of CSL Limited, which does not work with CD. All the other authors declare that they have no competing interests. Data and materials availability: Accession codes for data in Gene Expression Omnibus: GSE67014 includes GSE67011 and GSE67013.",
year = "2016",
month = apr,
day = "6",
doi = "10.1126/scitranslmed.aad6100",
language = "English (US)",
volume = "8",
journal = "Science translational medicine",
issn = "1946-6234",
publisher = "American Association for the Advancement of Science",
number = "333",
}