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Oxidized low-density lipoprotein stimulates macrophage 18F-FDG uptake via hypoxia-inducible factor-1α activation through Nox2-dependent reactive oxygen species generation.

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dc.contributor.authorLee, SJ-
dc.contributor.authorJung, KH-
dc.contributor.authorPaik, JY-
dc.contributor.authorLee, JH-
dc.contributor.authorPark, JW-
dc.contributor.authorLee, KH-
dc.date.accessioned2016-11-17T06:44:27Z-
dc.date.available2016-11-17T06:44:27Z-
dc.date.issued2014-
dc.identifier.issn0161-5505-
dc.identifier.urihttp://repository.ajou.ac.kr/handle/201003/12891-
dc.description.abstractFor (18)F-FDG PET to be widely used to monitor atherosclerosis progression and

therapeutic response, it is crucial to better understand how macrophage glucose

metabolism is influenced by the atherosclerotic microenvironment and to elucidate

the molecular mechanisms of this response. Oxidized low-density lipoprotein

(oxLDL) is a key player in atherosclerotic inflammation that promotes macrophage

recruitment, activation, and foam cell formation. We thus explored the effect of

oxLDL on macrophage (18)F-FDG uptake and investigated the underlying molecular

mechanism including the roles of hypoxia-inducible factor-1alpha (HIF-1alpha) and

reactive oxygen species (ROS). METHODS: RAW264.7 macrophages were stimulated with

native LDL, oxLDL, or lipopolysaccharide. Cells were assessed for (18)F-FDG

uptake, lactate production, membrane glucose transporter 1 (GLUT1) expression,

and hexokinase activity. ROS generation, Nox expression, and HIF-1alpha activity

were also measured. RESULTS: oxLDL (20 mug/mL) induced a 17.5 +/- 1.7-fold

increase in macrophage (18)F-FDG uptake by 24 h, which was accompanied by

increased lactate production, membrane GLUT1 expression, and hexokinase activity.

oxLDL-stimulated (18)F-FDG uptake was completely blocked by inhibitors of Src or

phosphoinositide 3-kinase. ROS generation was increased to 262.4% +/- 17.9% of

controls by oxLDL, and N-acetyl-l-cysteine completely abrogated both

oxLDL-induced ROS production and (18)F-FDG uptake. oxLDL increased Nox2

expression, and nicotinamide adenine dinucleotide phosphate oxidase inhibition

totally blocked increased ROS generation and (18)F-FDG uptake by oxLDL. Finally,

there was a clear ROS-dependent increase of HIF-1alpha accumulation by oxLDL, and

silencing of HIF-1alpha completely abolished the metabolic effect of oxLDL.

CONCLUSION: oxLDL is a strong stimulator of macrophage (18)F-FDG uptake and

glycolysis through upregulation of GLUT1 and hexokinase. This metabolic response

is mediated by Nox2-dependent ROS generation that promotes HIF-1alpha activation.
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dc.language.isoen-
dc.subject.MESHAnimals-
dc.subject.MESHCell Line-
dc.subject.MESHCell Membrane-
dc.subject.MESHDisease Progression-
dc.subject.MESHFluorodeoxyglucose F18-
dc.subject.MESHGlucose Transporter Type 1-
dc.subject.MESHHexokinase-
dc.subject.MESHHumans-
dc.subject.MESHHypoxia-Inducible Factor 1, alpha Subunit-
dc.subject.MESHLactic Acid-
dc.subject.MESHLipoproteins, LDL-
dc.subject.MESHMacrophages-
dc.subject.MESHMembrane Glycoproteins-
dc.subject.MESHMice, Inbred C57BL-
dc.subject.MESHNADPH Oxidase-
dc.subject.MESHRadiopharmaceuticals-
dc.subject.MESHReactive Oxygen Species-
dc.titleOxidized low-density lipoprotein stimulates macrophage 18F-FDG uptake via hypoxia-inducible factor-1α activation through Nox2-dependent reactive oxygen species generation.-
dc.typeArticle-
dc.identifier.pmid25214643-
dc.identifier.urlhttp://jnm.snmjournals.org/content/55/10/1699.long-
dc.contributor.affiliatedAuthor이, 수진-
dc.type.localJournal Papers-
dc.identifier.doi10.2967/jnumed.114.139428-
dc.citation.titleJournal of nuclear medicine-
dc.citation.volume55-
dc.citation.number10-
dc.citation.date2014-
dc.citation.startPage1699-
dc.citation.endPage1705-
dc.identifier.bibliographicCitationJournal of nuclear medicine, 55(10). : 1699-1705, 2014-
dc.identifier.eissn1535-5667-
dc.relation.journalidJ001615505-
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Nuclear Medicine & Molecular Imaging
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