title: Ursodeoxycholic acid impairs atherogenesis and promotes plaque regression by cholesterol crystal dissolution in mice.
abstract: Atherosclerosis is a chronic inflammatory disease driven primarily by a continuous retention of cholesterol within the subendothelial space where it precipitates to form cholesterol crystals (CC). These CC trigger a complex inflammatory response through activation of the NLRP3 inflammasome and promote lesion development. Here we examined whether increasing cholesterol solubility with ursodeoxycholic acid (UDCA) affects vascular CC formation and ultimately atherosclerotic lesion development. UDCA mediated intracellular CC dissolution in macrophages and reduced IL-1β production. In ApoE(-/-) mice, UDCA treatment not only impaired atherosclerotic plaque development but also mediated regression of established vascular lesions. Importantly, mice treated with UDCA had decreased CC-depositions in atherosclerotic plaques compared to controls. Together, our data demonstrate that UDCA impaired CC and NLRP3 dependent inflammation by increasing cholesterol solubility and diminished atherosclerosis in mice.
authors.affiliation: Medizinische Klinik und Poliklinik II, University Hospitals Bonn, 53105 Bonn, Germany.
authors.forename: Niklas
authors.initials: N
authors.lastname: Bode
authors.affiliation: Institute of Innate Immunity, University Hospitals Bonn, 53127 Bonn, Germany.
authors.forename: Alena
authors.initials: A
authors.lastname: Grebe
authors.affiliation: Institute of Clinical Chemistry und Clinical Pharmacology, University Hospitals Bonn, 53105 Bonn, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Kerksiek
authors.affiliation: Institute of Clinical Chemistry und Clinical Pharmacology, University Hospitals Bonn, 53105 Bonn, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Lütjohann
authors.affiliation: Medizinische Klinik und Poliklinik II, University Hospitals Bonn, 53105 Bonn, Germany.
authors.forename: Nikos
authors.initials: N
authors.lastname: Werner
authors.affiliation: Medizinische Klinik und Poliklinik II, University Hospitals Bonn, 53105 Bonn, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Nickenig
authors.affiliation: Institute of Innate Immunity, University Hospitals Bonn, 53127 Bonn, Germany; Department of Infectious Diseases and Immunology, UMass Medical School, Worcester, MA 01605, USA; German Center of Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany.
authors.forename: Eicke
authors.initials: E
authors.lastname: Latz
authors.affiliation: Medizinische Klinik und Poliklinik II, University Hospitals Bonn, 53105 Bonn, Germany. Electronic address: sebastian.zimmer@ukb.uni-bonn.de.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Zimmer
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D002756:Cholagogues and Choleretics / Q000008:administration & dosage; D002784:Cholesterol / Q000737:chemistry / Q000378:metabolism*; D003460:Crystallization; D004305:Dose-Response Relationship, Drug; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D016896:Treatment Outcome; D014580:Ursodeoxycholic Acid / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D002756:Cholagogues and Choleretics; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D014580:Ursodeoxycholic Acid; D002784:Cholesterol
keywords: Atherosclerosis; Cholesterol crystals; Cholesterol efflux capacity; IL-1β; NLRP3; Ursodeoxycholic acid