Results

RDF/XMLNTriplesTurtleShow queryShare ▶
SubjectPredicateObject
http://purl.uniprot.org/citations/23599441http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/23599441http://www.w3.org/2000/01/rdf-schema#comment"

Objective

Hypoxia is intimately linked to atherosclerosis and has become recognized as a primary impetus of inflammation. We recently demonstrated that the neuroimmune guidance cue netrin-1 (Ntn1) inhibits macrophage emigration from atherosclerotic plaques, thereby fostering chronic inflammation. However, the mechanisms governing netrin-1 expression in atherosclerosis are not well understood. In this study, we investigate the role of hypoxia in regulating expression of netrin-1 and its receptor uncoordinated-5-B receptor (Unc5b) in plaque macrophages and its functional consequences on these immune cells.

Approach and results

We show by immunostaining that netrin-1 and Unc5b are expressed in macrophages in hypoxia-rich regions of human and mouse plaques. In vitro, Ntn1 and Unc5b mRNA are upregulated in macrophages treated with oxidized low-density lipoprotein or inducers of oxidative stress (CoCl2, dimethyloxalylglycine, 1% O2). These responses are abrogated by inhibiting hypoxia-inducible transcription factor (HIF)-1α, indicating a causal role for this transcription factor in regulating Ntn1 and Unc5b expression in macrophages. Indeed, using promoter-luciferase reporter genes, we show that Ntn1- and Unc5b-promoter activities are induced by oxidized low-density lipoprotein and require HIF-1α. Correspondingly, J774 macrophages overexpressing active HIF-1α show increased netrin-1 and Unc5b expression and reduced migratory capacity compared with control cells, which was restored by blocking the effects of netrin-1. Finally, we show that netrin-1 protects macrophages from apoptosis under hypoxic conditions in a HIF-1α-dependent manner.

Conclusions

These findings provide a molecular mechanism by which netrin-1 and its receptor Unc5b are expressed in atherosclerotic plaques and implicate hypoxia and HIF-1α-induced netrin-1/Unc5b in sustaining inflammation by inhibiting the emigration and promoting the survival of lesional macrophages."xsd:string
http://purl.uniprot.org/citations/23599441http://purl.org/dc/terms/identifier"doi:10.1161/atvbaha.112.301008"xsd:string
http://purl.uniprot.org/citations/23599441http://purl.uniprot.org/core/author"Guo L."xsd:string
http://purl.uniprot.org/citations/23599441http://purl.uniprot.org/core/author"Yang Y."xsd:string
http://purl.uniprot.org/citations/23599441http://purl.uniprot.org/core/author"Moore K.J."xsd:string
http://purl.uniprot.org/citations/23599441http://purl.uniprot.org/core/author"Fisher E.A."xsd:string
http://purl.uniprot.org/citations/23599441http://purl.uniprot.org/core/author"Ramkhelawon B."xsd:string
http://purl.uniprot.org/citations/23599441http://purl.uniprot.org/core/author"Rayner K.J."xsd:string
http://purl.uniprot.org/citations/23599441http://purl.uniprot.org/core/author"van Gils J.M."xsd:string
http://purl.uniprot.org/citations/23599441http://purl.uniprot.org/core/author"Parathath S."xsd:string
http://purl.uniprot.org/citations/23599441http://purl.uniprot.org/core/author"Hewing B."xsd:string
http://purl.uniprot.org/citations/23599441http://purl.uniprot.org/core/author"Feig J.L."xsd:string
http://purl.uniprot.org/citations/23599441http://purl.uniprot.org/core/author"Oldebeken S."xsd:string
http://purl.uniprot.org/citations/23599441http://purl.uniprot.org/core/date"2013"xsd:gYear
http://purl.uniprot.org/citations/23599441http://purl.uniprot.org/core/name"Arterioscler Thromb Vasc Biol"xsd:string
http://purl.uniprot.org/citations/23599441http://purl.uniprot.org/core/pages"1180-1188"xsd:string
http://purl.uniprot.org/citations/23599441http://purl.uniprot.org/core/title"Hypoxia induces netrin-1 and Unc5b in atherosclerotic plaques: mechanism for macrophage retention and survival."xsd:string
http://purl.uniprot.org/citations/23599441http://purl.uniprot.org/core/volume"33"xsd:string
http://purl.uniprot.org/citations/23599441http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/23599441
http://purl.uniprot.org/citations/23599441http://xmlns.com/foaf/0.1/primaryTopicOfhttps://pubmed.ncbi.nlm.nih.gov/23599441
http://purl.uniprot.org/uniprot/#_B0QZL0-mappedCitation-23599441http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/23599441
http://purl.uniprot.org/uniprot/#_O09118-mappedCitation-23599441http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/23599441
http://purl.uniprot.org/uniprot/#_Q8IZJ1-mappedCitation-23599441http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/23599441
http://purl.uniprot.org/uniprot/Q8IZJ1http://purl.uniprot.org/core/mappedCitationhttp://purl.uniprot.org/citations/23599441
▶