Eukaryotic elongation factor 2 kinase regulates foam cell formation via translation of CD36

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dc.contributor.authorFernando, S.
dc.contributor.authorSalagaras, T.
dc.contributor.authorSchwarz, N.
dc.contributor.authorSandeman, L.
dc.contributor.authorTan, J.T.M.
dc.contributor.authorXie, J.
dc.contributor.authorZareh, J.
dc.contributor.authorJensen, K.
dc.contributor.authorWilliamson, A.
dc.contributor.authorDimasi, C.
dc.contributor.authorChhay, P.
dc.contributor.authorToledo-Flores, D.
dc.contributor.authorLong, A.
dc.contributor.authorManavis, J.
dc.contributor.authorWorthington, M.
dc.contributor.authorFitridge, R.
dc.contributor.authorDi Bartolo, B.A.
dc.contributor.authorBursill, C.A.
dc.contributor.authorNicholls, S.J.
dc.contributor.authorProud, C.G.
dc.contributor.authoret al.
dc.date.issued2022
dc.description.abstractEukaryotic elongation factor 2 kinase (eEF2K) is an atypical protein kinase that controls protein synthesis in cells under stress. Although well studied in cancer, less is known about its roles in chronic inflammatory diseases. Here, we examined its regulation of macrophage cholesterol handling in the context of atherosclerosis. eEF2K mRNA expression and protein activity were upregulated in murine bone marrow-derived macrophages (BMDMs) exposed to oxidized low-density lipoprotein cholesterol (oxLDL). When incubated with oxLDL, BMDMs from eEF2K knockout (Eef2k-/- ) mice formed fewer Oil Red O+ foam cells than Eef2k+/+ BMDMs (12.5% ± 2.3% vs. 32.3% ± 2.0%, p < .01). Treatment with a selective eEF2K inhibitor, JAN-384, also decreased foam cell formation for C57BL/6J BMDMs and human monocyte-derived macrophages. Disabling eEF2K selectively decreased protein expression of the CD36 cholesterol uptake receptor, mediated by a reduction in the proportion of translationally active Cd36 mRNA. Eef2k-/- mice bred onto the Ldlr-/- background developed aortic sinus atherosclerotic plaques that were 30% smaller than Eef2k+/+ -Ldlr-/- mice after 16 weeks of high cholesterol diet (p < .05). Although accompanied by a reduction in plaque CD36+ staining (p < .05) and lower CD36 expression in circulating monocytes (p < .01), this was not associated with reduced lipid content in plaques as measured by oil red O staining. Finally, EEF2K and CD36 mRNA levels were higher in blood mononuclear cells from patients with coronary artery disease and recent myocardial infarction compared to healthy controls without coronary artery disease. These results reveal a new role for eEF2K in translationally regulating CD36 expression and foam cell formation in macrophages. Further studies are required to explore therapeutic targeting of eEF2K in atherosclerosis.
dc.description.statementofresponsibilitySanuja Fernando, Thalia Salagaras, Nisha Schwarz, Lauren Sandeman, Joanne T. M. Tan, Jianling Xie ... et al.
dc.identifier.citationThe FASEB Journal, 2022; 36(2):1-19
dc.identifier.doi10.1096/fj.202101034R
dc.identifier.issn0892-6638
dc.identifier.issn1530-6860
dc.identifier.orcidTan, J.T.M. [0000-0003-1875-4882]
dc.identifier.orcidJensen, K. [0000-0002-2084-1734]
dc.identifier.orcidWilliamson, A. [0000-0003-3446-9248]
dc.identifier.orcidManavis, J. [0000-0001-7381-7781] [0000-0003-1268-561X]
dc.identifier.orcidFitridge, R. [0000-0001-6258-5997]
dc.identifier.orcidDi Bartolo, B.A. [0000-0001-8420-0461]
dc.identifier.orcidBursill, C.A. [0000-0002-0682-8760] [0000-0003-1087-7781]
dc.identifier.orcidNicholls, S.J. [0000-0002-9668-4368]
dc.identifier.orcidProud, C.G. [0000-0003-0704-6442]
dc.identifier.orcidPsaltis, P.J. [0000-0003-0222-5468]
dc.identifier.urihttps://hdl.handle.net/2440/134428
dc.language.isoen
dc.publisherFederation of American Society of Experimental Biology
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1142794
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1161506
dc.rights© 2022 Federation of American Societies for Experimental Biology
dc.source.urihttps://doi.org/10.1096/fj.202101034r
dc.subjectCD36
dc.subjectatherosclerosis
dc.subjecteEF2K
dc.subjectfoam cells
dc.subjectmacrophages
dc.subjectprotein translation
dc.subject.meshAnimals
dc.subject.meshAtherosclerosis
dc.subject.meshCD36 Antigens
dc.subject.meshCholesterol
dc.subject.meshCoronary Artery Disease
dc.subject.meshElongation Factor 2 Kinase
dc.subject.meshFemale
dc.subject.meshFoam Cells
dc.subject.meshHumans
dc.subject.meshLeukocytes, Mononuclear
dc.subject.meshMacrophages
dc.subject.meshMale
dc.subject.meshMice
dc.subject.meshMice, Inbred C57BL
dc.subject.meshMice, Knockout
dc.subject.meshMonocytes
dc.subject.meshPlaque, Atherosclerotic
dc.subject.meshRNA, Messenger
dc.subject.meshSignal Transduction
dc.titleEukaryotic elongation factor 2 kinase regulates foam cell formation via translation of CD36
dc.typeJournal article
pubs.publication-statusPublished

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