title: Liposomal prednisolone promotes macrophage lipotoxicity in experimental atherosclerosis.
abstract: Atherosclerosis is a lipid-driven inflammatory disease, for which nanomedicinal interventions are under evaluation. Previously, we showed that liposomal nanoparticles loaded with prednisolone (LN-PLP) accumulated in plaque macrophages, however, induced proatherogenic effects in patients. Here, we confirmed in low-density lipoprotein receptor knockout (LDLr(-/-)) mice that LN-PLP accumulates in plaque macrophages. Next, we found that LN-PLP infusions at 10mg/kg for 2weeks enhanced monocyte recruitment to plaques. In follow up, after 6weeks of LN-PLP exposure we observed (i) increased macrophage content, (ii) more advanced plaque stages, and (iii) larger necrotic core sizes. Finally, in vitro studies showed that macrophages become lipotoxic after LN-PLP exposure, exemplified by enhanced lipid loading, ER stress and apoptosis. These findings indicate that liposomal prednisolone may paradoxically accelerate atherosclerosis by promoting macrophage lipotoxicity. Hence, future (nanomedicinal) drug development studies are challenged by the multifactorial nature of atherosclerotic inflammation.
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Meibergdreef 9, Amsterdam, The Netherlands. Electronic address: f.m.valkvander@amc.nl.
authors.forename: Fleur M
authors.initials: FM
authors.lastname: van der Valk
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Meibergdreef 9, Amsterdam, The Netherlands; Department of Internal Medicine I, University Schleswig-Holstein, Arnold-Heller-Straße 3, Kiel, Germany. Electronic address: dominik.schulte@uksh.de.
authors.forename: Dominik M
authors.initials: DM
authors.lastname: Schulte
authors.affiliation: Experimental Vascular Biology, Department of Medical Biochemistry, Academic Medical Center, Meibergdreef 9, Amsterdam, The Netherlands. Electronic address: s.u.meiler@amc.uva.nl.
authors.forename: Svenja
authors.initials: S
authors.lastname: Meiler
authors.affiliation: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave, NY, USA. Electronic address: jun.tang.mssm@gmail.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Tang
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Meibergdreef 9, Amsterdam, The Netherlands. Electronic address: k.h.zheng@amc.uva.nl.
authors.forename: Kang He
authors.initials: KH
authors.lastname: Zheng
authors.affiliation: Experimental Vascular Biology, Department of Medical Biochemistry, Academic Medical Center, Meibergdreef 9, Amsterdam, The Netherlands. Electronic address: j.vandenbossche@amc.uva.nl.
authors.forename: Jan
authors.initials: J
authors.lastname: Van den Bossche
authors.affiliation: Experimental Vascular Biology, Department of Medical Biochemistry, Academic Medical Center, Meibergdreef 9, Amsterdam, The Netherlands. Electronic address: t.t.seijkens@amc.uva.nl.
authors.forename: Tom
authors.initials: T
authors.lastname: Seijkens
authors.affiliation: Department of Internal Medicine I, University Schleswig-Holstein, Arnold-Heller-Straße 3, Kiel, Germany. Electronic address: matthias.laudes@uk-sh.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Laudes
authors.affiliation: Experimental Vascular Biology, Department of Medical Biochemistry, Academic Medical Center, Meibergdreef 9, Amsterdam, The Netherlands. Electronic address: m.dewinther@amc.uva.nl.
authors.forename: Menno
authors.initials: M
authors.lastname: de Winther
authors.affiliation: Experimental Vascular Biology, Department of Medical Biochemistry, Academic Medical Center, Meibergdreef 9, Amsterdam, The Netherlands. Electronic address: e.lutgens@amc.uva.nl.
authors.forename: Esther
authors.initials: E
authors.lastname: Lutgens
authors.affiliation: Department of Biomaterials Science and Technology, Targeted Therapeutics section, MIRA Institute, University of Twente, Drienerlolaan 5, NB, Enschede, The Netherlands. Electronic address: A.M.S.A.Alaarg@uu.nl.
authors.forename: Amr
authors.initials: A
authors.lastname: Alaarg
authors.affiliation: Department of Biomaterials Science and Technology, Targeted Therapeutics section, MIRA Institute, University of Twente, Drienerlolaan 5, NB, Enschede, The Netherlands. Electronic address: bart@enceladus.nl.
authors.forename: Josbert M
authors.initials: JM
authors.lastname: Metselaar
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Meibergdreef 9, Amsterdam, The Netherlands. Electronic address: g.m.dallinga@amc.uva.nl.
authors.forename: Geesje M
authors.initials: GM
authors.lastname: Dallinga-Thie
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Meibergdreef 9, Amsterdam, The Netherlands; Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave, NY, USA. Electronic address: wjmmulder@gmail.com.
authors.forename: Willem J M
authors.initials: WJ
authors.lastname: Mulder
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Meibergdreef 9, Amsterdam, The Netherlands. Electronic address: e.s.stroes@amc.uva.nl.
authors.forename: Erik S G
authors.initials: ES
authors.lastname: Stroes
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Meibergdreef 9, Amsterdam, The Netherlands. Electronic address: a.a.hamers@amc.uva.nl.
authors.forename: Anouk A J
authors.initials: AA
authors.lastname: Hamers
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D008081:Liposomes; D008264:Macrophages / Q000473:pathology; D051379:Mice; D058226:Plaque, Atherosclerotic; D011239:Prednisolone / Q000008:administration & dosage*
chemical_list: D008081:Liposomes; D011239:Prednisolone
keywords: Atherosclerosis; Liposomal nanoparticles; Lipotoxicity; Macrophages; Prednisolone