Liposomal prednisolone promotes macrophage lipotoxicity in experimental atherosclerosis

Fleur M van der Valk; Dominik M Schulte; Svenja Meiler; Jun Tang; Kang He Zheng; Jan Van den Bossche; Tom Seijkens; Matthias Laudes; Menno de Winther; Esther Lutgens; Amr Alaarg; Josbert M Metselaar; Geesje M Dallinga-Thie; Willem J M Mulder; Erik S G Stroes; Anouk A J Hamers

doi:10.1016/j.nano.2016.02.022

Liposomal prednisolone promotes macrophage lipotoxicity in experimental atherosclerosis

Nanomedicine. 2016 Aug;12(6):1463-70. doi: 10.1016/j.nano.2016.02.022. Epub 2016 Mar 23.

Authors

Fleur M van der Valk¹, Dominik M Schulte², Svenja Meiler³, Jun Tang⁴, Kang He Zheng⁵, Jan Van den Bossche⁶, Tom Seijkens⁷, Matthias Laudes⁸, Menno de Winther⁹, Esther Lutgens¹⁰, Amr Alaarg¹¹, Josbert M Metselaar¹², Geesje M Dallinga-Thie¹³, Willem J M Mulder¹⁴, Erik S G Stroes¹⁵, Anouk A J Hamers¹⁶

Affiliations

¹ Department of Vascular Medicine, Academic Medical Center, Meibergdreef 9, Amsterdam, The Netherlands. Electronic address: [email protected].
² 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: [email protected].
³ Experimental Vascular Biology, Department of Medical Biochemistry, Academic Medical Center, Meibergdreef 9, Amsterdam, The Netherlands. Electronic address: [email protected].
⁴ Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave, NY, USA. Electronic address: [email protected].
⁵ Department of Vascular Medicine, Academic Medical Center, Meibergdreef 9, Amsterdam, The Netherlands. Electronic address: [email protected].
⁶ Experimental Vascular Biology, Department of Medical Biochemistry, Academic Medical Center, Meibergdreef 9, Amsterdam, The Netherlands. Electronic address: [email protected].
⁷ Experimental Vascular Biology, Department of Medical Biochemistry, Academic Medical Center, Meibergdreef 9, Amsterdam, The Netherlands. Electronic address: [email protected].
⁸ Department of Internal Medicine I, University Schleswig-Holstein, Arnold-Heller-Straße 3, Kiel, Germany. Electronic address: [email protected].
⁹ Experimental Vascular Biology, Department of Medical Biochemistry, Academic Medical Center, Meibergdreef 9, Amsterdam, The Netherlands. Electronic address: [email protected].
¹⁰ Experimental Vascular Biology, Department of Medical Biochemistry, Academic Medical Center, Meibergdreef 9, Amsterdam, The Netherlands. Electronic address: [email protected].
¹¹ Department of Biomaterials Science and Technology, Targeted Therapeutics section, MIRA Institute, University of Twente, Drienerlolaan 5, NB, Enschede, The Netherlands. Electronic address: [email protected].
¹² Department of Biomaterials Science and Technology, Targeted Therapeutics section, MIRA Institute, University of Twente, Drienerlolaan 5, NB, Enschede, The Netherlands. Electronic address: [email protected].
¹³ Department of Vascular Medicine, Academic Medical Center, Meibergdreef 9, Amsterdam, The Netherlands. Electronic address: [email protected].
¹⁴ 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: [email protected].
¹⁵ Department of Vascular Medicine, Academic Medical Center, Meibergdreef 9, Amsterdam, The Netherlands. Electronic address: [email protected].
¹⁶ Department of Vascular Medicine, Academic Medical Center, Meibergdreef 9, Amsterdam, The Netherlands. Electronic address: [email protected].

PMID: 27015770
DOI: 10.1016/j.nano.2016.02.022

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.

Keywords: Atherosclerosis; Liposomal nanoparticles; Lipotoxicity; Macrophages; Prednisolone.

MeSH terms

Animals
Atherosclerosis / metabolism*
Atherosclerosis / pathology*
Humans
Liposomes
Macrophages / pathology
Mice
Plaque, Atherosclerotic
Prednisolone / administration & dosage*

Substances

Liposomes
Prednisolone