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dc.contributor.authorBabaev, V. R.en_US
dc.contributor.authorYeung, M.en_US
dc.contributor.authorErbay, E.en_US
dc.contributor.authorDing, L.en_US
dc.contributor.authorZhang, Y.en_US
dc.contributor.authorMay, J. M.en_US
dc.contributor.authorFazio, S.en_US
dc.contributor.authorHotamisligil, G. S.en_US
dc.contributor.authorLinton, M. F.en_US
dc.date.accessioned2018-04-12T11:04:40Z
dc.date.available2018-04-12T11:04:40Z
dc.date.issued2016en_US
dc.identifier.issn1079-5642
dc.identifier.urihttp://hdl.handle.net/11693/37164
dc.description.abstractObjective - The c-Jun NH 2 -terminal kinases (JNK) are regulated by a wide variety of cellular stresses and have been implicated in apoptotic signaling. Macrophages express 2 JNK isoforms, JNK1 and JNK2, which may have different effects on cell survival and atherosclerosis. Approach and Results - To dissect the effect of macrophage JNK1 and JNK2 on early atherosclerosis, Ldlr-/- mice were reconstituted with wild-type, Jnk1-/-, and Jnk2-/- hematopoietic cells and fed a high cholesterol diet. Jnk1-/- →Ldlr-/- mice have larger atherosclerotic lesions with more macrophages and fewer apoptotic cells than mice transplanted with wild-type or Jnk2-/- cells. Moreover, genetic ablation of JNK to a single allele (Jnk1+/- /Jnk2-/- or Jnk1-/- /Jnk2+/-) in marrow of Ldlr-/- recipients further increased atherosclerosis compared with Jnk1-/- →Ldlr-/- and wild-type→Ldlr-/- mice. In mouse macrophages, anisomycin-mediated JNK signaling antagonized Akt activity, and loss of Jnk1 gene obliterated this effect. Similarly, pharmacological inhibition of JNK1, but not JNK2, markedly reduced the antagonizing effect of JNK on Akt activity. Prolonged JNK signaling in the setting of endoplasmic reticulum stress gradually extinguished Akt and Bad activity in wild-type cells with markedly less effects in Jnk1-/- macrophages, which were also more resistant to apoptosis. Consequently, anisomycin increased and JNK1 inhibitors suppressed endoplasmic reticulum stress-mediated apoptosis in macrophages. We also found that genetic and pharmacological inhibition of phosphatase and tensin homolog abolished the JNK-mediated effects on Akt activity, indicating that phosphatase and tensin homolog mediates crosstalk between these pathways. Conclusions - Loss of Jnk1, but not Jnk2, in macrophages protects them from apoptosis, increasing cell survival, and this accelerates early atherosclerosis.en_US
dc.language.isoEnglishen_US
dc.source.titleArteriosclerosis, Thrombosis, and Vascular Biologyen_US
dc.relation.isversionofhttp://dx.doi.org/10.1161/ATVBAHA.116.307580en_US
dc.subjectApoptosisen_US
dc.subjectAtherosclerosisen_US
dc.subjectEndoplasmic reticulum stressen_US
dc.subjectMacrophagesen_US
dc.subjectMAP kinase signaling systemen_US
dc.subjectAnisomycinen_US
dc.subjectAnthra[1,9 cd]pyrazol 6(2h) oneen_US
dc.subjectInsulinen_US
dc.subjectJNKI1en_US
dc.subjectLow density lipoprotein receptoren_US
dc.subjectMitogen activated protein kinase p38en_US
dc.subjectPhosphatidylinositol 3,4,5 trisphosphate 3 phosphataseen_US
dc.subjectProtein kinase Ben_US
dc.subjectStress activated protein kinase 1en_US
dc.subjectUnclassified drugen_US
dc.subjectBad protein, mouseen_US
dc.subjectLow density lipoprotein receptoren_US
dc.subjectMitogen activated protein kinase 9en_US
dc.subjectProtein BADen_US
dc.subjectProtein kinase Ben_US
dc.subjectProtein kinase inhibitoren_US
dc.subjectPten protein, mouseen_US
dc.subjectStress activated protein kinase 1en_US
dc.subjectAlleleen_US
dc.subjectAnimal cellen_US
dc.subjectAnimal experimenten_US
dc.subjectAnimal modelen_US
dc.subjectApoptosisen_US
dc.subjectArticleen_US
dc.subjectAtherosclerosisen_US
dc.subjectCholesterol dieten_US
dc.subjectControlled studyen_US
dc.subjectEndoplasmic reticulum stressen_US
dc.subjectEnzyme activityen_US
dc.subjectEnzyme deficiencyen_US
dc.subjectEnzyme inhibitionen_US
dc.subjectGene repressionen_US
dc.subjectHematopoietic cellen_US
dc.subjectMacrophageen_US
dc.subjectMouseen_US
dc.subjectNonhumanen_US
dc.subjectPriority journalen_US
dc.subjectSignal transductionen_US
dc.subjectAnimalen_US
dc.subjectAntagonists and inhibitorsen_US
dc.subjectAortaen_US
dc.subjectAortic diseaseen_US
dc.subjectApoptosisen_US
dc.subjectAtherosclerosisen_US
dc.subjectAtherosclerotic plaqueen_US
dc.subjectBone marrow cellen_US
dc.subjectBone marrow transplantationen_US
dc.subjectC57BL mouseen_US
dc.subjectCell cultureen_US
dc.subjectCell survivalen_US
dc.subjectDeficiencyen_US
dc.subjectDisease modelen_US
dc.subjectDrug effectsen_US
dc.subjectEnzymologyen_US
dc.subjectGenetic predispositionen_US
dc.subjectGeneticsen_US
dc.subjectHypercholesterolemiaen_US
dc.subjectKnockout mouseen_US
dc.subjectLipid dieten_US
dc.subjectMetabolismen_US
dc.subjectPathologyen_US
dc.subjectPhenotypeen_US
dc.subjectAnimalsen_US
dc.subjectAortaen_US
dc.subjectAortic Diseasesen_US
dc.subjectApoptosisen_US
dc.subjectAtherosclerosisen_US
dc.subjectBcl-Associated Death Proteinen_US
dc.subjectBone Marrow Cellsen_US
dc.subjectBone Marrow Transplantationen_US
dc.subjectCell Survivalen_US
dc.subjectCells, Cultureden_US
dc.subjectDiet, High-Faten_US
dc.subjectDisease Models, Animalen_US
dc.subjectEndoplasmic Reticulum Stressen_US
dc.subjectGenetic Predisposition to Diseaseen_US
dc.subjectHypercholesterolemiaen_US
dc.subjectMacrophagesen_US
dc.subjectInbred C57BLen_US
dc.subjectKnockouten_US
dc.subjectMitogen-Activated Protein Kinase 8en_US
dc.subjectMitogen-Activated Protein Kinase 9en_US
dc.subjectPhenotypeen_US
dc.subjectAtheroscleroticen_US
dc.subjectProtein Kinase Inhibitorsen_US
dc.subjectProto-Oncogene Proteins c-akten_US
dc.subjectPTEN Phosphohydrolaseen_US
dc.subjectReceptorsen_US
dc.subjectSignal Transductionen_US
dc.titleJnk1 deficiency in hematopoietic cells suppresses macrophage apoptosis and increases atherosclerosis in low-density lipoprotein receptor null miceen_US
dc.typeArticleen_US
dc.departmentDepartment of Molecular Biology and Geneticsen_US
dc.citation.spage1122en_US
dc.citation.epage1131en_US
dc.citation.volumeNumber36en_US
dc.citation.issueNumber6en_US
dc.identifier.doi10.1161/ATVBAHA.116.307580en_US
dc.publisherLippincott Williams and Wilkinsen_US


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