title: Preclinical Reversal of Atherosclerosis by FDA-Approved Compound that Transforms Cholesterol into an Anti-Inflammatory "Prodrug".
abstract: Although atherosclerosis is treatable with lipid-lowering drugs, not all patients respond. Hydroxypropyl-beta-cyclodextrin (CD) is an FDA-approved compound for solubilizing, capturing, and delivering lipophilic drugs in humans. Zimmer et al. report that CD mediates regression of atherosclerotic plaques in two mouse models by solubilizing cholesterol crystals (CCs), and promoting metabolism of CCs into water-soluble 27-hydroxycholesterol, which, in turn, activates anti-inflammatory LXR receptor target genes, promotes active and passive efflux of cholesterol from macrophages, and increases metabolic processing of cholesterol. In effect, CD inverts the role of its cargo, cholesterol, from inflammatory to anti-inflammatory by converting cholesterol into a "prodrug" that when modified to 27-hydroxycholesterol reduces atherosclerosis. This mechanism defines a new class of pharmaceuticals, "inverters": compounds that cause innate biomolecules to act opposite to their normal function. However, chronic CD treatment in animal models damages auditory cells, which must be addressed before CD can be developed as a systemic drug for atherosclerosis.
authors.affiliation: 1 Panorama Research Institute , Sunnyvale, California.|2 Regenerative Sciences Institute , Sunnyvale, California.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Mendelsohn
authors.affiliation: 1 Panorama Research Institute , Sunnyvale, California.|2 Regenerative Sciences Institute , Sunnyvale, California.
authors.forename: James W
authors.initials: JW
authors.lastname: Larrick
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002784:Cholesterol / Q000378:metabolism*; D004195:Disease Models, Animal; D018836:Inflammation Mediators / Q000378:metabolism*; D050356:Lipid Metabolism / Q000187:drug effects; D051379:Mice; D058226:Plaque, Atherosclerotic; D015398:Signal Transduction / Q000187:drug effects; D012995:Solubility; D047392:beta-Cyclodextrins / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D000924:Anticholesteremic Agents; D018836:Inflammation Mediators; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D002784:Cholesterol