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Sci Transl Med. 2016 Apr 6;8(333):333ra50. doi: 10.1126/scitranslmed.aad6100.

Cyclodextrin promotes atherosclerosis regression via macrophage reprogramming.

Author information

1
Medizinische Klinik und Poliklinik II, University Hospital Bonn, 53105 Bonn, Germany.
2
Institute of Innate Immunity, University Hospital Bonn, 53127 Bonn, Germany.
3
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.
4
Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, 0424 Oslo, Norway.
5
Genomics and Immunoregulation, Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany.
6
Department of Neurology, Oslo University Hospital Rikshospitalet, 0424 Oslo, Norway.
7
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.
8
Institute of Clinical Chemistry und Clinical Pharmacology, University Hospital Bonn, 53105 Bonn, Germany.
9
Addi and Cassi Fund, Reno, NV 89511, USA.
10
Clinic and Polyclinic for Neurology, University Hospital Bonn, 53105 Bonn, Germany.
11
Lipid Metabolism Unit, Center for Computational and Integrative Biology, Boston, MA 02114, USA.
12
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.
13
Division of Clinical Chemistry, Karolinska Institutet, Huddinge University Hospital, 141 86 Huddinge, Sweden.
14
Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77004, USA.
15
Department of Medicine, Columbia University, New York, NY 10032, USA.
16
CSL Behring, King of Prussia, PA 19406, USA.
17
Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, 7489 Trondheim, Norway.
18
German Center of Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany. Genomics and Immunoregulation, Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany.
19
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.

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.

PMID:
27053774
PMCID:
PMC4878149
DOI:
10.1126/scitranslmed.aad6100
[Indexed for MEDLINE]
Free PMC Article

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