Liposomal prednisolone promotes macrophage lipotoxicity in experimental atherosclerosis

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• 作者：Fleur M. van der Valk ; PhD ; MD^a ; ¹ ; ^{f.m.valkvander@amc.nl" class="auth_mail" title="E-mail the corresponding author} ; Dominik M. Schulte ; PhD ; MD^a ; ^b ; ¹ ; ^{dominik.schulte@uksh.de" class="auth_mail" title="E-mail the corresponding author} ; Svenja Meiler ; PhD^c ; ^{s.u.meiler@amc.uva.nl" class="auth_mail" title="E-mail the corresponding author} ; Jun Tang ; PhD^d ; ^{jun.tang.mssm@gmail.com" class="auth_mail" title="E-mail the corresponding author} ; Kang He Zheng ; PhD ; MD^a ; ^{k.h.zheng@amc.uva.nl" class="auth_mail" title="E-mail the corresponding author} ; Jan Van den Bossche ; PhD ; MSc^c ; ^{j.vandenbossche@amc.uva.nl" class="auth_mail" title="E-mail the corresponding author} ; Tom Seijkens ; PhD ; MD^c ; ^{t.t.seijkens@amc.uva.nl" class="auth_mail" title="E-mail the corresponding author} ; Matthias Laudes ; PhD ; MD^b ; ^{matthias.laudes@uk-sh.de" class="auth_mail" title="E-mail the corresponding author} ; Menno de Winther ; PhD ; MSc^c ; ^{m.dewinther@amc.uva.nl" class="auth_mail" title="E-mail the corresponding author} ; Esther Lutgens ; PhD ; MD^c ; ^{e.lutgens@amc.uva.nl" class="auth_mail" title="E-mail the corresponding author} ; Amr Alaarg ; PhD^e ; ^{A.M.S.A.Alaarg@uu.nl" class="auth_mail" title="E-mail the corresponding author} ; Josbert M. Metselaar ; PhD^e ; ^{bart@enceladus.nl" class="auth_mail" title="E-mail the corresponding author} ; Geesje M. Dallinga-Thie ; PhD^a ; ^{g.m.dallinga@amc.uva.nl" class="auth_mail" title="E-mail the corresponding author} ; Willem J.M. Mulder ; PhD ; MSc^a ; ^d ; ^{wjmmulder@gmail.com" class="auth_mail" title="E-mail the corresponding author} ; Erik S.G. Stroes ; PhD ; MD^a ; ^{e.s.stroes@amc.uva.nl" class="auth_mail" title="E-mail the corresponding author} ; Anouk A.J. Hamers ; PhD ; MSc^a ; ^{a.a.hamers@amc.uva.nl" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Atherosclerosis ; Macrophages ; Lipotoxicity ; Prednisolone ; Liposomal nanoparticles
• 刊名：Nanomedicine: Nanotechnology, Biology and Medicine
• 出版年：2016
• 出版时间：August 2016
• 年：2016
• 卷：12
• 期：6
• 页码：1463-1470
• 全文大小：1416 K

文摘

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.