Macrophage specific overexpression of the human macrophage scavenger receptor in transgenic mice, using a 180-kb yeast artificial chromosome, leads to enhanced foam cell formation of isolated peritoneal macrophages

Winther, Menno P.J. de; Dijk, Ko Willems van; Vlijmen, Bart J.M. van; Gijbels, Marion J.J.; Heus, J. J.; Wijers, E.; Bos, Alida C van den; Breuer, M.; Frants, Rune R.; Havekes, Louis M.; Hofker, Marten H.

doi:10.1016/s0021-9150(99)00204-x

Cited by 26 publications

(13 citation statements)

References 35 publications

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“…23 Another important issue is whether the capacity T-USPIO to target plaque phagocytotic activity in mice will be fully reflective of its targeting efficacy in a human context. Our data in a humanized model of atherosclerosis (ie, LDLr −/− mice with macrophage-specific overexpression of the human macrophage SR-A) 24,29,30 clearly confirm the imaging potential of PP1-equipped USPIO for human inflammatory plaques. From histological plaque analysis, we can exclude differences in lesion size or plaque characteristics between the different groups, confirming that the increased image contrast is attributable to increased T-USPIO ingestion by SR-AI-expressing plaque macrophages.…”

Section: Discussionsupporting

confidence: 70%

Scavenger Receptor-AI–Targeted Iron Oxide Nanoparticles for In Vivo MRI Detection of Atherosclerotic Lesions

Segers

Adel

Bot

et al. 2013

ATVB

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Objective-In search of molecular imaging modalities for specific detection of inflammatory atherosclerotic plaques, we explored the potential of targeting scavenger receptor-AI (SR-AI), which is highly expressed by lesional macrophages and linked to effective internalization machinery. Approach and Results-Ultrasmall superparamagnetic iron oxide particles were conjugated to a peptidic SR-AI ligand (0.371 mol Fe/L and 0.018 mol PP1/L). In vitro incubation of human or murine macrophages with SR-AI-targeted USPIO led to significantly higher iron uptake in vitro than with nontargeted USPIO, as judged by quantitative atomic absorption spectroscopy and Perl's staining. Incremental uptake was strictly mediated by SRs. SR-AI-targeted USPIO displayed accelerated plasma decay and a 3.5-fold increase (P=0.01) in atherosclerotic plaque accumulation on intravenous injection into apolipoprotein E-deficient mice compared with nontargeted USPIO. In addition, atherosclerotic humanized LDLr −/− chimeras with leukocyte expression of human SR-AI showed a significant improvement in contrast-to-noise ratio (2.7-fold; P=0.003) in the atherosclerotic aortic arch plaques 24 hours after injection of SR-AI-targeted USPIO compared with chimeras with leukocyte SR-AI deficiency. Conclusions-Collectively, our data provide several lines of evidence that SR-AI-targeted molecular imaging of USPIO-based contrast agents holds great promise for in situ detection of inflammatory plaques in manifest atherosclerosis. Segers et al SR-AI-Targeted Molecular Imaging of Atherosclerosis 1813screening that displayed high affinity and specificity for SR-AI in vitro in murine and human macrophages. In vivo, PP1 has been shown to accumulate in macrophage-rich organs where it colocalized with F4/80+ macrophages and in atherosclerotic plaques. Furthermore, intravenous injected PP1-coupled fluorescent nanocrystals were successfully accumulated in advanced atherosclerotic plaques of apolipoprotein E-deficient (apoE −/− ) mice. 19In the current study, we report development and validation of SR-AI-targeted USPIO (T-USPIO) functionalized with the aforementioned SR-AI-specific peptide. The T-USPIO was validated in vitro on different mouse and human cell types found in atherosclerotic lesions and also in vivo in an established mouse model for atherosclerosis, as well as in a humanized model of atherosclerosis. Materials and MethodsMaterials and Methods are available in the online-only Supplement. Results Relaxivity AnalysisThe contrast agent relaxivities were measured at 37°C at 20, 60, and 400 MHz, respectively (Table). The transverse relaxivities of the SR-A1 and control particle did not differ significantly nor did the longitudinal relaxivity. Increased Scavenger Receptor-AI-Mediated Uptake of T-USPIO In VitroThe kinetics of basal uptake, processing, and detection of USPIO in vitro and in vivo by macrophages have been the subject of numerous studies. 9 Here, we sought to investigate whether USPIO uptake by (plaque associated) macrophages could be augmented by conju...

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Section: Discussionsupporting

confidence: 70%

Scavenger Receptor-AI–Targeted Iron Oxide Nanoparticles for In Vivo MRI Detection of Atherosclerotic Lesions

Segers

Adel

Bot

et al. 2013

ATVB

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“…Cells were incubated for 24 h in culture medium with or without either 25 g/ml native LDL or 25 g/ml Cu 2 ϩ -oxidized LDL. Cholesteryl esters were determined as described before (29).…”

Section: In Vitro Foam Cell Formationmentioning

confidence: 99%

Macrophage-specific overexpression of group IIa sPLA2 increases atherosclerosis and enhances collagen deposition

Ghesquiere

Gijbels

Anthonsen

et al. 2005

Journal of Lipid Research

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“…74 We have found that isolated peritoneal macrophages from a recently generated mouse model overexpressing the human SRA gene also show an increased foam cell formation and cholesterol ester accumulation after incubation with acLDL. 75 Furthermore, the SRA has been shown to be highly expressed in atherosclerotic lesions, 76,77 whereas the SRA ligand, oxLDL, is present in plaques. [77][78][79] On the basis of these results, SRA has been assigned an important role in atherogenesis.…”

Section: Sra In Foam Cell Formation and Atherosclerosismentioning

confidence: 99%

“…Recently, we generated a mouse carrying the human SRA gene region as a 180-kb transgene. 75 Macrophages from these humane SRA transgenic mice (MSR1 mice) show a high expression of human SRA. This results in an increased degradation of acLDL and oxLDL in vitro.…”

Section: Sra In Foam Cell Formation and Atherosclerosismentioning

confidence: 99%

Macrophage Scavenger Receptor Class A

Winther

Dijk

Havekes

et al. 2000

ATVB

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213

101

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Abstract-In atherogenesis, elevated plasma levels of low density lipoprotein (LDL) lead to the chronic presence of LDL in the arterial wall. There, LDL is modified (eg, oxidized), and these modified lipoproteins activate endothelial cells, which attract circulating monocytes. These monocytes enter the vessel wall, differentiate into macrophages, and subject the modified lipoproteins to endocytosis through scavenger receptor pathways. This unrestricted uptake, which is not limited by intracellular cholesterol levels, eventually leads to the formation of lipid-filled foam cells, the initial step in atherosclerosis. Macrophage scavenger receptor class A (SRA) is thought to be one of the main receptors involved in foam cell formation, mediating the influx of lipids into the macrophages. In addition to this role in modified lipoprotein uptake by macrophages, the SRA has been shown to be important in the inflammatory response in host defense, cellular activation, adhesion, and cell-cell interaction. Given the importance of these processes in atherogenesis, these latter functions may prove to make the SRA a multifunctional player in the atherosclerotic process.

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Macrophage specific overexpression of the human macrophage scavenger receptor in transgenic mice, using a 180-kb yeast artificial chromosome, leads to enhanced foam cell formation of isolated peritoneal macrophages

Cited by 26 publications

References 35 publications

Scavenger Receptor-AI–Targeted Iron Oxide Nanoparticles for In Vivo MRI Detection of Atherosclerotic Lesions

Scavenger Receptor-AI–Targeted Iron Oxide Nanoparticles for In Vivo MRI Detection of Atherosclerotic Lesions

Macrophage-specific overexpression of group IIa sPLA2 increases atherosclerosis and enhances collagen deposition

Macrophage Scavenger Receptor Class A

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