Magnetic resonance imaging contrast-enhancement with superparamagnetic iron oxide nanoparticles amplifies macrophage foam cell apoptosis in human and murine atherosclerosis.

Autor:	Segers FME; Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden, The Netherlands.; Faculty of Medicine, Research Institute of Internal Medicine, University Hospital Oslo, Oslo, Norway., Ruder AV; Department of Pathology, CARIM School for Cardiovascular Sciences, Maastricht University Medical Center, Maastricht, The Netherlands., Westra MM; Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden, The Netherlands., Lammers T; Department of Nanomedicine and Theranostics, RWTH Aachen University, Aachen, Germany., Dadfar SM; Department of Nanomedicine and Theranostics, RWTH Aachen University, Aachen, Germany., Roemhild K; Department of Nanomedicine and Theranostics, RWTH Aachen University, Aachen, Germany.; Institute of Pathology, RWTH Aachen University, Aachen, Germany., Lam TS; Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden, The Netherlands., Kooi ME; Department of Radiology and Nuclear Medicine, CARIM School for Cardiovascular Sciences, Maastricht University Medical Center, Maastricht, The Netherlands., Cleutjens KBJM; Department of Pathology, CARIM School for Cardiovascular Sciences, Maastricht University Medical Center, Maastricht, The Netherlands., Verheyen FK; Molecular Cell Biology and Electron Microscopy (CRISP), Maastricht University Medical Center, Maastricht, The Netherlands., Schurink GWH; Department of Surgery, CARIM School for Cardiovascular Sciences, Maastricht University Medical Center, Maastricht, The Netherlands., Haenen GR; Department of Toxicology, Maastricht University Medical Center, Maastricht, The Netherlands., van Berkel TJC; Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden, The Netherlands., Bot I; Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden, The Netherlands., Halvorsen B; Faculty of Medicine, Research Institute of Internal Medicine, University Hospital Oslo, Oslo, Norway., Sluimer JC; Department of Pathology, CARIM School for Cardiovascular Sciences, Maastricht University Medical Center, Maastricht, The Netherlands.; Cardiovascular Sciences, Edinburgh University, Edinburgh, UK., Biessen EAL; Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden, The Netherlands.; Department of Pathology, CARIM School for Cardiovascular Sciences, Maastricht University Medical Center, Maastricht, The Netherlands.; Institute for Molecular Cardiovascular Research, RWTH Aachen University, Aachen, Germany.
Jazyk:	angličtina
Zdroj:	Cardiovascular research [Cardiovasc Res] 2023 Jan 18; Vol. 118 (17), pp. 3346-3359.
DOI:	10.1093/cvr/cvac032
Abstrakt:	Aims: (Ultra) Small superparamagnetic iron oxide nanoparticles, (U)SPIO, are widely used as magnetic resonance imaging contrast media and assumed to be safe for clinical applications in cardiovascular disease. As safety tests largely relied on normolipidaemic models, not fully representative of the clinical setting, we investigated the impact of (U)SPIOs on disease-relevant endpoints in hyperlipidaemic models of atherosclerosis. Methods and Results: RAW264.7 foam cells, exposed in vitro to ferumoxide (dextran-coated SPIO), ferumoxtran (dextran-coated USPIO), or ferumoxytol [carboxymethyl (CM) dextran-coated USPIO] (all 1 mg Fe/mL) showed increased apoptosis and reactive oxygen species accumulation for ferumoxide and ferumoxtran, whereas ferumoxytol was tolerated well. Pro-apoptotic (TUNEL+) and pro-oxidant activity of ferumoxide (0.3 mg Fe/kg) and ferumoxtran (1 mg Fe/kg) were confirmed in plaque, spleen, and liver of hyperlipidaemic ApoE-/- (n = 9/group) and LDLR-/- (n = 9-16/group) mice that had received single IV injections compared with saline-treated controls. Again, ferumoxytol treatment (1 mg Fe/kg) failed to induce apoptosis or oxidative stress in these tissues. Concomitant antioxidant treatment (EUK-8/EUK-134) largely prevented these effects in vitro (-68%, P < 0.05) and in plaques from LDLR-/- mice (-60%, P < 0.001, n = 8/group). Repeated ferumoxtran injections of LDLR-/- mice with pre-existing atherosclerosis enhanced plaque inflammation and apoptosis but did not alter plaque size. Strikingly, carotid artery plaques of endarterectomy patients who received ferumoxtran (2.6 mg Fe/kg) before surgery (n = 9) also showed five-fold increased apoptosis (18.2 vs. 3.7%, respectively; P = 0.004) compared with controls who did not receive ferumoxtran. Mechanistically, neither coating nor particle size seemed accountable for the observed cytotoxicity of ferumoxide and ferumoxtran. Conclusions: Ferumoxide and ferumoxtran, but not ferumoxytol, induced apoptosis of lipid-laden macrophages in human and murine atherosclerosis, potentially impacting disease progression in patients with advanced atherosclerosis. Competing Interests: Conflicts of interest: The principal investigator (E.A.L.B.) has received financial support for this work from Guerbet. This manuscript was handled by Consulting Editor Alain Tedgui. (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)
Databáze:	MEDLINE
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