Cyclodextrin promotes atherosclerosis regression via LXR activation (I). Mus musculus

Atherosclerosis is an inflammatory disease linked to elevated blood cholesterol levels. Despite ongoing advances in the prevention and treatment of atherosclerosis 1, cardiovascular disease remains the leading cause of death worldwide 2. Continuous retention of apolipoprotein B-containing lipoproteins in the subendothelial space causes a local overabundance of free cholesterol. Since cholesterol accumulation and deposition of cholesterol crystals (CCs) triggers a complex inflammatory response 3 4, we tested the therapeutic potential of increasing cholesterol solubility in experimental atherogenesis. Here we show that treatment of murine atherosclerosis with the cyclic oligosaccharide 2-hydroxypropyl-β-cyclodextrin (CD), a compound that solubilizes lipophilic substances, reduced atherosclerotic plaque size, cholesterol crystal load and promoted plaque regression even under continuing Western diet. CD solubilized CCs and promoted cholesterylester and oxysterol production in macrophages leading to liver X receptor (LXR)-mediated transcriptional reprogramming. CD increased cholesterol efflux from macrophages and substantially augmented reverse cholesterol transport in vivo. Furthermore, CD reduced proinflammatory cytokines in vivo and decreased macrophage responsiveness towards TLR and inflammasome activation. Since CD treatment in humans is safe and CD beneficially affects key pathogenetic factors in atherogenesis it may thus be used clinically to prevent or treat human atherosclerosis . Overall design: We hypothesize that cyclodextrin (CD) treatment of mice results in activation of LXR transcription factors, which is described to be antiatherogenic. To test whether LXR activation by CD contributes to the anti-atherogenic effects of CD, LDLR knockout mice were transplanted with bone-marrow of wt or LXRa/LXRb dko mice. The mice were put on a high-fat diet for 8 weeks and subcutaneously treated with cyclodextrin (CD) or a vehicle control as described in the methods part of the paper. Snap-frozen descending aortas of these mice were used for gene expression analysis.