[en] 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.
Disciplines :
Neurology
Author, co-author :
Zimmer, Sebastian; Medizinische Klinik und Poliklinik II, University Hospital Bonn, 53105 Bonn, Germany
Grebe, Alena; Institute of Innate Immunity, University Hospital Bonn, 53127 Bonn, Germany
Bakke, Siril S; Institute of Innate Immunity, University Hospital Bonn, 53127 Bonn, Germany. German Center of Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany. Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, 7489 Trondheim, Norway
Bode, Niklas; Medizinische Klinik und Poliklinik II, University Hospital Bonn, 53105 Bonn, Germany
Halvorsen, Bente; Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, 0424 Oslo, Norway
Ulas, Thomas; Genomics and Immunoregulation, Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany
Skjelland, Mona; Department of Neurology, Oslo University Hospital Rikshospitalet, 0424 Oslo, Norway
De Nardo, Dominic; Institute of Innate Immunity, University Hospital Bonn, 53127 Bonn, Germany. Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia. Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia
Labzin, Larisa I; Institute of Innate Immunity, University Hospital Bonn, 53127 Bonn, Germany
Kerksiek, Anja; Institute of Clinical Chemistry und Clinical Pharmacology, University Hospital Bonn, 53105 Bonn, Germany
Hempel, Chris; Addi and Cassi Fund, Reno, NV 89511, USA
HENEKA, Michael ; Clinic and Polyclinic for Neurology, University Hospital Bonn, 53105 Bonn, Germany
Hawxhurst, Victoria; Lipid Metabolism Unit, Center for Computational and Integrative Biology, Boston, MA 02114, USA
Fitzgerald, Michael L; Lipid Metabolism Unit, Center for Computational and Integrative Biology, Boston, MA 02114, USA
Trebicka, Jonel; Medizinische Klinik und Poliklinik I, University Hospital Bonn, 53105 Bonn, Germany. Faculty of Health Sciences, University of Southern Denmark Campusvej 55, DK-5230 Odense M, Denmark
Björkhem, Ingemar; Division of Clinical Chemistry, Karolinska Institutet, Huddinge University Hospital, 141 86 Huddinge, Sweden
Gustafsson, Jan-Åke; Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77004, USA
Westerterp, Marit; Department of Medicine, Columbia University, New York, NY 10032, USA
Tall, Alan R; Department of Medicine, Columbia University, New York, NY 10032, USA
Wright, Samuel D; CSL Behring, King of Prussia, PA 19406, USA
Espevik, Terje; Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, 7489 Trondheim, Norway
Schultze, Joachim L; German Center of Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany. Genomics and Immunoregulation, Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany
Nickenig, Georg; Medizinische Klinik und Poliklinik II, University Hospital Bonn, 53105 Bonn, Germany
Lütjohann, Dieter; Institute of Clinical Chemistry und Clinical Pharmacology, University Hospital Bonn, 53105 Bonn, Germany
Latz, Eicke; Institute of Innate Immunity, University Hospital Bonn, 53127 Bonn, Germany. German Center of Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany. Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, 7489 Trondheim, Norway. Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA. eicke.latz@uni-bonn.de
NIH Research Council of Norway Robert A. Welch Foundation Swedish Science Council Deutsche Forschungsgemeinschaft DFG
Funding text :
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-Sørensen (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.-Å.G.);the Swedish Science Council (H2416223; to J.-Å.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.-Å.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.
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