title: The Effect of Low-Dose Proteasome Inhibition on Pre-Existing Atherosclerosis in LDL Receptor-Deficient Mice.
abstract: Dysfunction of the ubiquitin-proteasome system (UPS) has been implicated in atherosclerosis development. However, the nature of UPS dysfunction has been proposed to be specific to certain stages of atherosclerosis development, which has implications for proteasome inhibition as a potential treatment option. Recently, low-dose proteasome inhibition with bortezomib has been shown to attenuate early atherosclerosis in low-density lipoprotein receptor-deficient (LDLR-/-) mice. The present study investigates the effect of low-dose proteasome inhibition with bortezomib on pre-existing advanced atherosclerosis in LDLR-/-mice. We found that bortezomib treatment of LDLR-/-mice with pre-existing atherosclerosis does not alter lesion burden. Additionally, macrophage infiltration of aortic root plaques, total plasma cholesterol levels, and pro-inflammatory serum markers were not influenced by bortezomib. However, plaques of bortezomib-treated mice exhibited larger necrotic core areas and a significant thinning of the fibrous cap, indicating a more unstable plaque phenotype. Taking recent studies on favorable effects of proteasome inhibition in early atherogenesis into consideration, our data support the hypothesis of stage-dependent effects of proteasome inhibition in atherosclerosis.
authors.affiliation: Medizinische Klinik für Kardiologie und Angiologie, Charité-Universitätsmedizin Berlin, Campus Mitte, 10117 Berlin, Germany. nicola.wilck@charite.de.|Experimental and Clinical Research Center, a Joint Cooperation between the Charité-Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany. nicola.wilck@charite.de.|DZHK, German Center for Cardiovascular Disease, Partner Site Berlin, 10115 Berlin, Germany. nicola.wilck@charite.de.
authors.forename: Nicola
authors.initials: N
authors.lastname: Wilck
authors.affiliation: Medizinische Klinik für Kardiologie und Angiologie, Charité-Universitätsmedizin Berlin, Campus Mitte, 10117 Berlin, Germany. m.fechner@medizin-im-gruenen.de.
authors.forename: Mandy
authors.initials: M
authors.lastname: Fechner
authors.affiliation: Medizinische Klinik für Kardiologie und Angiologie, Charité-Universitätsmedizin Berlin, Campus Mitte, 10117 Berlin, Germany. cristian.dan@charite.de.
authors.forename: Cristian
authors.initials: C
authors.lastname: Dan
authors.affiliation: Medizinische Klinik für Kardiologie und Angiologie, Charité-Universitätsmedizin Berlin, Campus Mitte, 10117 Berlin, Germany. verena.stangl@charite.de.|DZHK, German Center for Cardiovascular Disease, Partner Site Berlin, 10115 Berlin, Germany. verena.stangl@charite.de.
authors.forename: Verena
authors.initials: V
authors.lastname: Stangl
authors.affiliation: Medizinische Klinik für Kardiologie und Angiologie, Charité-Universitätsmedizin Berlin, Campus Mitte, 10117 Berlin, Germany. karl.stangl@charite.de.|DZHK, German Center for Cardiovascular Disease, Partner Site Berlin, 10115 Berlin, Germany. karl.stangl@charite.de.
authors.forename: Karl
authors.initials: K
authors.lastname: Stangl
authors.affiliation: Medizinische Klinik für Kardiologie und Angiologie, Charité-Universitätsmedizin Berlin, Campus Mitte, 10117 Berlin, Germany. antje.ludwig@charite.de.|DZHK, German Center for Cardiovascular Disease, Partner Site Berlin, 10115 Berlin, Germany. antje.ludwig@charite.de.
authors.forename: Antje
authors.initials: A
authors.lastname: Ludwig
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D000069286:Bortezomib / Q000008:administration & dosage* / Q000494:pharmacology; D002784:Cholesterol / Q000097:blood; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D061988:Proteasome Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D011973:Receptors, LDL / Q000172:deficiency*
chemical_list: D016207:Cytokines; D061988:Proteasome Inhibitors; D011973:Receptors, LDL; D000069286:Bortezomib; D002784:Cholesterol
keywords: atherosclerosis; inflammation; proteasome inhibition