ECE2016 Eposter Presentations Cardiovascular Endocrinology and Lipid Metabolism (51 abstracts)
Liposomal prednisolone promotes macrophage necroptosis in experimental atherosclerosis: does this explain atherogenesis in Cushing’s disease?
Dominik M Schulte 1, , Fleur M van der Valk 1 , Svenja Meiler 3 , Jun Tang 4 , Kang He Zheng 1 , Jan van den Bossche 3 , Tom Seijkens 3 , Matthias Laudes 2 , Menno de Winther 3 , Esther Lutgens 3 , Amr Alaarg 5 , Josbert M Metselaar 5 , Geesje M Dallinga-Thie 1 , Willem J M Mulder 1, , Erik S G Stroes 1 & Anouk A J Hamers 1
1Department of Vascular Medicine, AMC, Amsterdam, The Netherlands; 2Department of Internal Medicine I, UKSH, Kiel, Germany; 3Experimental Vascular Biology, Department of Medical Biochemistry, AMC, Amsterdam, The Netherlands; 4Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, USA; 5Department of Biomaterials Science and Technology, Targeted Therapeutics section, MIRA Institute, University of Twente, Enschede, The Netherlands.
Introduction: Patients with a Cushing syndrome – a glucocorticoid driven disease–have a high risk for cardiovascular events, mainly due to atherosclerosis. Atherosclerosis is a lipid-driven inflammatory disease, for which novel anti-inflammatory strategies like glucocorticoids are under evaluation. Thus, the impact of glucocorticoids on atherosclerosis seems to be ambiguous: pro- or anti-inflammatory. To avoid systemic glucocorticoid side effects contributing to atherosclerosis liposomal nanoparticles loaded with prednisolone phosphate (LN-PLP) can directly target the side of atherosclerosis. We aimed to unravel the direct effects of LN-PLP on macrophages residing in the lipid-rich environment of atherosclerosis.
Description of methods/design: Low-density lipoprotein receptor knockout (LDLr−/−) mice were fed a high fat diet. Biweekly injections of LN-PLP at 10 mg/kg have been performed over 2 and 6 weeks. Post mortem, local delivery and intrinsic effects of LN-PLP have been studied on the aortic tissue. In vitro, murine and human macrophages were exposed to LN-PLP to study the effect of lipid trafficking endoplasmatic reticulum (ER) stress and apoptosis.
Results: We show that LN-PLP accumulated in plaque macrophages and enhanced monocyte recruitment to atherosclerotic plaques after 2 weeks, followed by increased macrophage content, more advanced plaque stages, and larger necrotic core sizes after 6 weeks of LN-PLP administration. In vitro, murine and human macrophages polarize into a lipid-avid phenotype after LN-PLP exposure, leading to increased lipid accumulation, ER stress and necroptosis.
Conclusions: These findings indicate that macrophage targeting in plaques with prednisolone may accelerate atherosclerosis by promoting macrophage lipotoxicity and necroptosis, thereby highlighting the challenges of anti-inflammatory therapy in atherosclerosis. This model might explain atherogenesis in Cushing’s disease and unravel new mechanisms than can be used for medical treatment reducing the cardio-vascular risk of these patients.
Volume 41
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Endocrine Abstracts
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