Cyclodextrin promotes atherosclerosis regression via macrophage reprogramming

Maybe 50 years from now this will be far enough along to actually be a treatment. But only if our fucking failures of stroke associations are destroyed and replaced with survivor focused ones with real leaders and strategies.
http://stm.sciencemag.org/content/8/333/333ra50

1. Sebastian Zimmer¹,*,
2. Alena Grebe²,*,
3. Siril S. Bakke²,³,⁴,
4. Niklas Bode¹,
5. Bente Halvorsen⁵,
6. Thomas Ulas⁶,
7. Mona Skjelland⁷,
8. Dominic De Nardo²,⁸,⁹,
9. Larisa I. Labzin²,
10. Anja Kerksiek¹⁰,
11. Chris Hempel¹¹,
12. Michael T. Heneka¹²,
13. Victoria Hawxhurst¹³,
14. Michael L. Fitzgerald¹³,
15. Jonel Trebicka¹⁴,¹⁵,
16. Ingemar Björkhem¹⁶,
17. Jan-Åke Gustafsson¹⁷,
18. Marit Westerterp¹⁸,
19. Alan R. Tall¹⁸,
20. Samuel D. Wright¹⁹,
21. Terje Espevik⁴,
22. Joachim L. Schultze³,⁶,
23. Georg Nickenig¹,
24. Dieter Lütjohann¹⁰ and
25. Eicke Latz²,³,⁴,²⁰,†

+ Author Affiliations

1. ↵†Corresponding author. E-mail: eicke.latz@uni-bonn.de

• ↵* These authors contributed equally to this work.

Science Translational Medicine  06 Apr 2016:
Vol. 8, Issue 333, pp. 333ra50
DOI: 10.1126/scitranslmed.aad6100

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Dissolving away cholesterol

Cardiovascular disease resulting from atherosclerosis is one of the most common causes of death worldwide, and additional therapies for this disease are greatly needed because not all patients can be effectively treated with existing approaches. Cyclodextrin is a common FDA-approved substance that is already used as a solubilizing agent to improve delivery of various drugs. Now, Zimmer et al. have discovered that cyclodextrin can also solubilize cholesterol, removing it from plaques, dissolving cholesterol crystals, and successfully treating atherosclerosis in a mouse model. Because cyclodextrin is already known to be safe in humans, this drug is now a potential candidate for testing in human patients for the treatment of atherosclerosis.

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.