Grebe, Alena: Targeting cholesterol crystals in atherosclerosis with cholesterol solubilizing 2-hydroxypropyl-β-cyclodextrin. - Bonn, 2016. - Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn.
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5n-45247
@phdthesis{handle:20.500.11811/6912,
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5n-45247,
author = {{Alena Grebe}},
title = {Targeting cholesterol crystals in atherosclerosis with cholesterol solubilizing 2-hydroxypropyl-β-cyclodextrin},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2016,
month = dec,

note = {Atherosclerosis is the underlying pathology of cardiovascular diseases (CVDs), the leading cause of deaths worldwide. Elevated blood cholesterol levels have been linked to this slowly progressing inflammatory disease and lowering the amount of circulating low-density lipoprotein (LDL) cholesterol is one of the most successful treatment approaches. Crystalline cholesterol deposits in the vessel wall are a hallmark of advanced atherosclerotic plaques, but they actually already occur in early stages of atherosclerosis development. Cholesterol crystals (CCs) can activate the NLRP3 inflammasome, a cytosolic multimolecular signaling complex present in innate immune cells, such as macrophages, which are the most prominent cell type in the developing atherosclerotic plaque. NLRP3 inflammasome activation results in the release of the pro-inflammatory cytokines IL-1β and IL-18, which are key contributors to the vascular inflammation driving atherosclerosis progression. Therefore, presumably a reduction in the amount of CCs in atherosclerotic plaques could also decrease vascular inflammation and consequently atherosclerosis progression.
In this study, whether 2-hydroxypropyl-β-cyclodextrin (CD), a compound that solubilizes cholesterol and removes cholesterol from cells, is effective in reducing vascular CC deposition or removing CCs from atherosclerotic plaques and thereby preventing atherosclerosis development was investigated in mice. CD treatment indeed impaired murine atherosclerosis development, which was indicated by a reduction of atherosclerotic plaque size and CC load. Moreover, CD treatment even mediated the regression of already established atherosclerotic plaques. The molecular mechanisms of CD-mediated atheroprotection were further examined in vitro in macrophages. CD treatment of CC-loaded macrophages mediated the dissolution of intracellular CCs and subsequently promoted crystal-derived cholesterol esterification, efflux and metabolism to oxysterols such as 27-hydroxycholesterol. Some oxysterols function as endogenous agonists for liver X receptor (LXR) transcription factors, which in turn activate genes regulating cholesterol efflux and antiinflammatory processes. Indeed, CD treatment induced LXR-mediated transcriptional reprogramming of macrophages towards increased cholesterol efflux. Thereby, CD promoted the reverse cholesterol transport and excretion of crystal-derived cholesterol from CC-loaded macrophages in an LXR-dependent manner. Moreover, LXR transcription factor activation was required for the atheroprotective and anti-inflammatory effects of CD in vivo in murine atherosclerosis.
This study shows that CD is atheroprotective in mice by dissolving and removing CCs from atherosclerotic plaques and by promoting the production of cholesterol-derived endogenous LXR agonists that activate anti-atherogenic transcriptional processes. Since CD treatment is already approved for clinical use by the U.S. food and drug administration (FDA), it could be directly tested in clinical trials for the prevention or treatment of human atherosclerosis.},

url = {http://hdl.handle.net/20.500.11811/6912}
}

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