| Experiment Id | GSE67013 | Name | Cyclodextrin promotes atherosclerosis regression via LXR activation (II) |
| Experiment Type | transcription profiling by array | Study Type | WT vs. Mutant |
| Source | GEO | Curation Date | 2024-04-11 |
| description | Atherosclerosis is an inflammatory disease linked to elevated blood cholesterol levels. 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. Since cholesterol accumulation and deposition of cholesterol crystals (CCs) triggers a complex inflammatory response, 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-beta-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. We hypothesize that cyclodextrin (CD) reprograms macrophage gene expression by activating LXR transcription factors. Therefore, we used M-CSF derived bone-marrow macrophages from wt and LXRa/LXRb dko mice, which were loaded with cholesterol crystals for 3h or left untreated. Excess cholesterol crystals were washed away and the BMDMs were treated for 4h with 10 mM of CD prior to gene expression analysis. |
