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

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

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	1463-1470
Number of pages	8
Journal	Nanomedicine : nanotechnology, biology and medicine
Volume	12
Issue number	6
DOIs	https://doi.org/10.1016/j.nano.2016.02.022
Publication status	Published - 2016

Keywords

Atherosclerosis
Macrophages
Lipotoxicity
Prednisolone
Liposomal nanoparticles

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10.1016/j.nano.2016.02.022

1-s2.0-S1549963416300144-mainFinal published version, 1.38 MBLicence: Taverne

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van der Valk, F. M., Schulte, D. M., Meiler, S., Tang, J., Zheng, K. H., Van den Bossche, J., Seijkens, T., Laudes, M., de Winther, M., Lutgens, E., Alaarg, A., Metselaar, J. M., Dallinga-Thie, G. M., Mulder, W. J. M., Stroes, E. S. G., & Hamers, A. A. J. (2016). Liposomal prednisolone promotes macrophage lipotoxicity in experimental atherosclerosis. Nanomedicine : nanotechnology, biology and medicine, 12(6), 1463-1470. https://doi.org/10.1016/j.nano.2016.02.022

@article{6f5b28fc0aa748f1901fe8d01de2e55e,

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.",

keywords = "Atherosclerosis, Macrophages, Lipotoxicity, Prednisolone, Liposomal nanoparticles",

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

note = "Copyright {\textcopyright} 2016. Published by Elsevier Inc.",

year = "2016",

doi = "10.1016/j.nano.2016.02.022",

language = "English",

volume = "12",

pages = "1463--1470",

journal = "Nanomedicine : nanotechnology, biology and medicine",

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van der Valk, FM, Schulte, DM, Meiler, S, Tang, J, Zheng, KH, Van den Bossche, J, Seijkens, T, Laudes, M, de Winther, M, Lutgens, E, Alaarg, A, Metselaar, JM, Dallinga-Thie, GM, Mulder, WJM, Stroes, ESG & Hamers, AAJ 2016, 'Liposomal prednisolone promotes macrophage lipotoxicity in experimental atherosclerosis', Nanomedicine : nanotechnology, biology and medicine, vol. 12, no. 6, pp. 1463-1470. https://doi.org/10.1016/j.nano.2016.02.022

TY - JOUR

T1 - Liposomal prednisolone promotes macrophage lipotoxicity in experimental atherosclerosis

AU - van der Valk, Fleur M

AU - Schulte, Dominik M

AU - Meiler, Svenja

AU - Tang, Jun

AU - Zheng, Kang He

AU - Van den Bossche, Jan

AU - Seijkens, Tom

AU - Laudes, Matthias

AU - de Winther, Menno

AU - Lutgens, Esther

AU - Alaarg, Amr

AU - Metselaar, Josbert M

AU - Dallinga-Thie, Geesje M

AU - Mulder, Willem J M

AU - Stroes, Erik S G

AU - Hamers, Anouk A J

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

KW - Atherosclerosis

KW - Macrophages

KW - Lipotoxicity

KW - Prednisolone

KW - Liposomal nanoparticles

U2 - 10.1016/j.nano.2016.02.022

DO - 10.1016/j.nano.2016.02.022

M3 - Article

C2 - 27015770

SN - 1549-9634

VL - 12

SP - 1463

EP - 1470

JO - Nanomedicine : nanotechnology, biology and medicine

JF - Nanomedicine : nanotechnology, biology and medicine

IS - 6

ER -

Liposomal prednisolone promotes macrophage lipotoxicity in experimental atherosclerosis

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Keywords

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