Cyclodextrin promotes atherosclerosis regression via macrophage reprogramming

Sebastian Zimmer, Alena Grebe, Siril S Bakke, Niklas Bode, Bente Halvorsen, Thomas Ulas, Mona Skjelland, Dominic De Nardo, Larisa I Labzin, Anja Kerksiek, Chris Hempel, Michael T Heneka, Victoria Hawxhurst, Michael L Fitzgerald, Jonel Trebicka, Ingemar Björkhem, Jan-Åke Gustafsson, Marit Westerterp, Alan R Tall, Samuel D WrightTerje Espevik, Joachim L Schultze, Georg Nickenig, Dieter Lütjohann, Eicke Latz

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Abstrakt

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.

OriginalsprogEngelsk
TidsskriftScience Translational Medicine
Vol/bind8
Udgave nummer333
Sider (fra-til)333ra50
ISSN1946-6234
DOI
StatusUdgivet - 6. apr. 2016

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Citationsformater

Zimmer, S., Grebe, A., Bakke, S. S., Bode, N., Halvorsen, B., Ulas, T., Skjelland, M., De Nardo, D., Labzin, L. I., Kerksiek, A., Hempel, C., Heneka, M. T., Hawxhurst, V., Fitzgerald, M. L., Trebicka, J., Björkhem, I., Gustafsson, J-Å., Westerterp, M., Tall, A. R., ... Latz, E. (2016). Cyclodextrin promotes atherosclerosis regression via macrophage reprogramming. Science Translational Medicine, 8(333), 333ra50. https://doi.org/10.1126/scitranslmed.aad6100