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Cell response to imaging contrast agents suggested for atherosclerotic plaque imaging
Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Oxysterols are the major cytotoxic components of oxidized low-density lipoprotein (OxLDL) that accumulate in atherosclerotic plaques. Their uptake by macrophages ensue foam cell formation, atherogenesis and plaque progression. Magnetic resonance imaging (MRI) has grown as a modality to track such intra-plaque developments by using intracellular contrast agents. The focus of this study was to evaluate the effects of two contrast agents; manganese based mangafodipir (TeslascanTM) and iron based super-paramagnetic iron oxide nanoparticles (SPION, ResovistTM) on cell functions and examined their interaction with oxysterol laden cells.

Mangafodipir has antioxidant property and provides protection against oxidative stress. The chemical structure of mangafodipir comprises of organic ligand fodipir (Dipyridoxyl diphosphate, Dp-dp) and Mn (manganese). Mangafodipir is readily metabolized within the body to manganese dipyridoxyl ethyldiamine (MnPLED) after an intravenous injection. MnPLED has superoxide dismutase (SOD) mimetic activity, and Dp-dp has iron chelating effects. The second contrast agent tested in this study is ResovistTM. These SPION are primarily ingested by macrophages and accumulated in lysosomes where they are gradually degraded ensuing increased cellular iron.

In paper I, we examined whether the above-noted effects of mangafodipir could be utilized to prevent 7β-hydroxycholesterol (7βOH) induced cell death. We found that mangafodipir prevents 7βOH induced cell death by attenuating reactive oxygen species (ROS) and by preserving lysosomal membrane integrity and mitochondrial membrane potential.

The second part of this study (paper II) was designed to identify the pharmacologically active part of mangafodipir, which exerts the above-noted effects. We compared the activity of parent compound (mangafodipir) with MnPLED and Dp-dp. We found that mangafodipir; MnPLED and Dp-dp provide similar cyto-protection against 7βOH induced cell death. These results suggest that MnPLED and Dp-dp both contribute to the pharmacologically active part of mangafodipir.

In paper III, we aimed to examine the interaction of SPION with monocytes and macrophages exposed or not to atheroma relevant oxysterols. We demonstrate that SPION loading up-regulates cellular levels of cathepsin and ferritin and induces membranous ferroportin expression. Additionally, SPION incites secretion of ferritin and both pro-inflammatory and anti-inflammatory cytokines. Moreover, exposure to oxysterols resulted in a reduced SPION uptake by cells, which may lead to inefficient targeting of such cells. Although SPION uptake was reduced, the ingested amounts significantly up-regulated the expression of 7βOH induced cathepsin B, cathepsin L and ferritin in cells, which may further aggravate atherogenesis.

The fourth part of the study (paper IV) was designed to examine the interaction of SPION with macrophage subtypes and compare the cellular effects of coated and uncoated iron-oxide nanoparticles. We found that iron in SPION induces a phenotypic shift in THP1 M2 macrophages towards a macrophage subtype characterized by upregulated intracellular levels of CD86, ferritin and cathepsin L. Differential levels of these proteins among macrophage subtypes might be important to sustain a functional plasticity. Additionally, uncoated iron-oxide nanoparticles induced dose dependent cell death in macrophages, which elucidates the potential cyto-toxicity of iron in iron-oxide nanoparticles.

In conclusion, evidence is provided in this study that intracellular MRI contrast agents have the potential to modulate cell functions. The study reveals a therapeutic potential of mangafodipir, which could be utilized for future development of contrast agents with both diagnostic and curative potentials. Additionally, we found that surface coating in SPION may provide cell tolerance to iron toxicity by modulation of cellular iron metabolism and cell functions. Such alterations in cellular metabolism call for careful monitoring and also highlight new concepts for development of iron containing nanoparticles. A reduced uptake of SPION by atheroma relevant cells justifies development of functionalized SPION to target such cells in atherosclerotic plaques.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2013. , 73 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1357
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-92003ISBN: 978-91-7519-671-8 (print)OAI: oai:DiVA.org:liu-92003DiVA: diva2:619962
Public defence
2013-05-31, Nils Holger, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 13:00 (English)
Opponent
Supervisors
Available from: 2013-05-07 Created: 2013-05-07 Last updated: 2013-05-07Bibliographically approved
List of papers
1. Prevention of 7beta-hydroxycholesterol-induced cell death by mangafodipir is mediated through lysosomal and mitochondrial pathways
Open this publication in new window or tab >>Prevention of 7beta-hydroxycholesterol-induced cell death by mangafodipir is mediated through lysosomal and mitochondrial pathways
2010 (English)In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, no 640, 124-128 p.Article in journal (Refereed) Published
Abstract [en]

Mangafodipir, a MRI contrast agent, has been used as a viability marker in patients with myocardial infarction and showed vascular relaxation effect. It confers myocardial protection against oxidative stress. However mechanisms underlying such protection have not yet been investigated. In this investigation we first studied whether mangafodipir inhibits apoptosis induced by 7beta-hydroxycholesterol (7betaOH), a cytotoxic cholesterol oxidation product found in atherosclerotic lesions in humans and in heart of ethanol-fed rats. We then focused on whether mangafodipir influences the production of reactive oxygen species, lysosomal and mitochondrial membrane permeabilities in the cell model. Our results revealed that pre-treatment with mangafodipir (400microM) protected against cellular reactive oxygen species production, apoptosis, and permeabilization of lysosomal and mitochondrial membranes induced by 7betaOH. In conclusion, a novel effect of mangafodipir on 7betaOH-induced apoptosis is via reduction of cellular reactive oxygen species and stabilization of lysosomal and mitochondrial membranes. This is the first report to show the additional cytoprotective effect of mangafodipir, which may suggest possible use of the drug.

Keyword
Atherosclerosis, Apoptosis, Mangafodipir, Oxidized lipid, Oxidative stress
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-57355 (URN)10.1016/j.ejphar.2010.04.046 (DOI)20452343 (PubMedID)
Available from: 2010-06-17 Created: 2010-06-17 Last updated: 2017-12-12
2. Fodipir (Dp-dp) and its dephosphorylated derivative PLED are involved in mangafodipir mediated cyto-protection against 7β-hydroxycholesterol induced cell death
Open this publication in new window or tab >>Fodipir (Dp-dp) and its dephosphorylated derivative PLED are involved in mangafodipir mediated cyto-protection against 7β-hydroxycholesterol induced cell death
2013 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Mangafodipir exerts pharmacological effects, including vascular relaxation and protection against oxidative stress and cell death induced by oxysterols. Additionally, mangafodipir has been proposed for cardiovascular imaging. The primary metabolite of mangafodipir, manganese dipyridoxyl ethyldiamine (MnPLED) and its constituent, dipyridoxyl diphosphate (Dp-dp) also known as fodipir, are pharmacologically active. However, whether they affect oxysterol induced cytotoxicity is currently unknown. In this study, we examine whether the mangafodipir metabolite affects 7β-hydroxycholesterol (7βOH) induced cell death and identify the underlying mechanisms. U937 cells were pre-treated or not with mangafodipir substrate (Ms) (200 μm), MnPLED (100 μM) or Dp-dp (100 μM) for 8 hours and then exposed to 7βOH (28 μM) for 18 hours. Our results revealed that pre-treatment with MnPLED or Dp-dp protected against 7βOH induced cellular reactive oxygen species (ROS) production, apoptosis, and lysosomal membrane permeabilization (LMP). MnPLED and Dpdp in par with Ms, confer protection against 7βOH induced cytotoxicity by reducing  cellular ROS and stabilization of lysosomal membrane. These results suggest that, fodipir is the active part in mangafodipir, which shows the noted effects and its activity is conserved in MnPLED. These results further confirm the cyto-protective effect of mangafodipir and justify its potential use as a cyto-protective adjuvant.

Keyword
Atherogenic, Apoptosis, Mangafodipir, Oxidative stress, Oxysterols
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-91996 (URN)
Available from: 2013-05-07 Created: 2013-05-07 Last updated: 2013-05-07Bibliographically approved
3. Degradation of superparamagnetic iron oxide nanoparticle-induced ferritin by lysosomal cathepsins and related immune response
Open this publication in new window or tab >>Degradation of superparamagnetic iron oxide nanoparticle-induced ferritin by lysosomal cathepsins and related immune response
Show others...
2012 (English)In: Nanomedicine, ISSN 1743-5889, E-ISSN 1748-6963, Vol. 7, no 5, 705-717 p.Article in journal (Refereed) Published
Abstract [en]

Aim: To examine the physiological impact of superparamagnetic iron oxide nanoparticles (SPIONs) on cell function and its interaction with oxysterol laden cells. Materials andamp; methods: Intracellular iron was determined by Prussian blue staining. Cellular ferritin, cathepsin L and ferroportin were analyzed by flow cytometry and fluorescence microscopy. Cytokine secretion was determined by ELISA and immunoblotting. Results: In U937 and THP 1 cells, we did not detect any loss of cell viability on SPION loading. Desferrioxamine prevents induction of both ferritin and cathepsin L by SPIONs. Inhibition of lysosomal cathepsins upregulates both endogenous- and SPION-induced ferritin. SPION loading induces membranous ferroportin and incites secretion of ferritin, TNF-alpha and IL-10. 7 beta-hydroxycholesterol exposure reduces SPION uptake by cells. Conclusion: SPION loading results in upregulation of lysosomal cathepsin, membranous ferroportin and ferritin degradation, which is associated with secretion of both pro- and anti-inflammatory cytokines. A reduced SPION uptake by oxysterol-laden cells may lead to a compromised MRI with elevated cathepsins and ferritin.

Place, publisher, year, edition, pages
Future Medicine, 2012
Keyword
atherosclerosis, cytokine, degradation, iron, lysosomal, monocyte, nanoparticle
National Category
Engineering and Technology
Identifiers
urn:nbn:se:liu:diva-78580 (URN)10.2217/nnm.11.148 (DOI)000304238300016 ()
Note

Funding Agencies|Swedish Heart Lung Foundation||research fund of Torsten och Ragnar Soderbergs||research fund of Stroke||research fund of Gamla Tjanarinnor||Linkoping University Hospital||

Available from: 2012-06-15 Created: 2012-06-15 Last updated: 2017-12-07
4. SPION primes THP1 derived M2 macrophages towards M1-like macrophages
Open this publication in new window or tab >>SPION primes THP1 derived M2 macrophages towards M1-like macrophages
2013 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 441, no 4, 737-742 p.Article in journal (Refereed) Published
Abstract [en]

Potentially, cellular iron regulates functional plasticity in macrophages yet; interaction of functionally polarized macrophages with iron-oxide nanoparticles has never been studied. We found that monocyte differentiation alters cellular ferritin and cathepsin L levels and induces functional polarization in macrophages. Iron in super paramagnetic iron-oxide nanoparticle (SPION) induces a phenotypic shift in THP1 derived M2 macrophages towards a high CD86+ macrophage subtype. This phenotypic shift was accompanied by up-regulated intracellular levels of ferritin and cathepsin L in M2 macrophages, which we found as a characteristic hallmark of M1 macrophages. Atherogenic oxysterols reduce phagocytic activity in both macrophage subtypes and thus these cells may escape detection by ironoxide nanoparticles (INPs) in-vivo.

Place, publisher, year, edition, pages
Elsevier, 2013
Keyword
Cathepsin L; Ferritin; Iron-oxide nanoparticles; M1 and M2 macrophages; Oxysterols
National Category
Immunology
Identifiers
urn:nbn:se:liu:diva-91999 (URN)10.1016/j.bbrc.2013.10.115 (DOI)000328434800008 ()
Available from: 2013-05-07 Created: 2013-05-07 Last updated: 2017-12-06Bibliographically approved

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