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.
N1 - Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/8/1
Y1 - 2016/8/1
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 10 mg/kg for 2 weeks enhanced monocyte recruitment to plaques. In follow up, after 6 weeks 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 10 mg/kg for 2 weeks enhanced monocyte recruitment to plaques. In follow up, after 6 weeks 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 - Liposomal nanoparticles
KW - Lipotoxicity
KW - Macrophages
KW - Prednisolone
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U2 - 10.1016/j.nano.2016.02.022
DO - 10.1016/j.nano.2016.02.022
M3 - Article
C2 - 27015770
AN - SCOPUS:84965002334
SN - 1549-9634
VL - 12
SP - 1463
EP - 1470
JO - Nanomedicine: Nanotechnology, Biology, and Medicine
JF - Nanomedicine: Nanotechnology, Biology, and Medicine
IS - 6
ER -